TW201524958A - Novel compounds used as rearrangement inhibitors during transfection - Google Patents

Abstract

The present invention relates to a novel compound which is an inhibitor of rearrangement (RET) kinase during transfection, and relates to a pharmaceutical composition containing the same, a process for the preparation thereof, and a medical use thereof, which may be used singly or in combination. Recovering normal gastrointestinal susceptibility, motility and/or secretion and/or abdominal lesions or diseases, and/or treatments for diseases associated with RET dysfunction or that may result in medical benefits from modulation of RET activity, such diseases Including (but not limited to): all types of intestinal irritation (IBS), including diarrhea, constipation or alternating fecal type; functional flatulence, functional constipation, functional diarrhea, unclear functional bowel disease , functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disease, functional gastric and duodenal lesions, functional anorectal pain, inflammatory bowel disease; proliferative diseases such as non-small cell lung cancer, hepatocytes Carcinoma, colorectal cancer, medullary thyroid carcinoma, follicular thyroid cancer, thyroid undifferentiated carcinoma, mastoid thyroid cancer, brain tumor, peritoneal cancer, solid tumor, other lung , head and neck cancer, glioma, neuroblastoma, Von Hippel-Lindau Syndrome, and kidney, breast, fallopian tube, ovarian, transitional epithelial, prostate Cancer, esophagus and gastroesophageal junction cancer, gallbladder and adenocarcinoma, and any malignant disease that increases RET kinase activity.

Description

Novel compounds used as rearrangement inhibitors during transfection

The present invention relates to a novel compound which is an inhibitor of rearrangement (RET) kinase during transfection, and relates to a pharmaceutical composition containing the same, a process for the preparation thereof, and a medical use thereof, which may be used singly or in combination. Recovering normal gastrointestinal susceptibility, motility and/or secretion and/or abdominal lesions or diseases, and/or treatments for diseases associated with RET dysfunction or that may result in medical benefits from modulation of RET activity, such diseases Including (but not limited to): all types of intestinal irritation (IBS), including diarrhea, constipation or alternating fecal type; functional flatulence, functional constipation, functional diarrhea, unclear functional bowel disease , functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disease, functional gastric and duodenal lesions, functional anorectal pain, inflammatory bowel disease, proliferative diseases such as non-small cell lung cancer, hepatocytes Carcinoma, colorectal cancer, medullary thyroid carcinoma, follicular thyroid cancer, thyroid undifferentiated carcinoma, mastoid thyroid cancer, brain tumor, peritoneal cancer, solid tumor, other lung , head and neck cancer, glioma, neuroblastoma, Von Hippel-Lindau Syndrome, and kidney, breast, fallopian tube, ovarian, transitional epithelial, prostate Cancer, esophagus and gastroesophageal junction cancer, gallbladder and adenocarcinoma, and any malignant disease that increases RET kinase activity.

Intestinal irritability (IBS) is a common disease affecting 10-20% of individuals in developed countries and is characterized by abnormal intestinal habits, flatulence and excessive organ sensitivity (Camilleri, M., N. Engl. J. Med., 2012, 367: 1626-1635). Although the cause of IBS is unknown, it is thought to be due to lesions between the brain and the gastrointestinal tract, intestinal microbial disorders or increased inflammation. The resulting gastrointestinal changes can affect normal bowel movements, causing diarrhea or constipation. In addition, in most patients with IBS, sensitization of the peripheral nervous system can cause excessive organ sensitivity or tactile pain (Keszthelyi, D., Eur. J. Pain, 2012, 16: 1444-1454).

Although IBS does not directly change life expectancy, it has a great impact on the quality of life of patients. In addition, the health care costs associated with IBS are high and often lose productivity due to absentee work (Nellesen, D. et al., J. Manag. Care Pharm., 2013, 19: 755-764). One of the most important symptoms affecting the quality of life of patients with IBS is organ pain (Spiegel, B. et al., Am. J. Gastroenterol., 2008, 103: 2536-2543). Molecular stratification methods that inhibit IBS-related organ pain can significantly affect the quality of life of patients with IBS and reduce associated costs.

Rearrangement (RET) during transfection is a neuronal growth factor receptor tyrosine kinase that is involved in one of four neurotropic factors (glial cell-derived neurotropic factor (GDNF), neuron rank protein, artemisia The combination of artemin and persephin with the combination of the co-receptor GDNF family receptors α-1, 2, 3, and 4, respectively, is activated (Plaza-Menacho, I. et al. Trends) Genet., 2006, 22: 627-636). RET is known to play an important role in the development and survival of afferent pain receptors in the skin and intestines. Mice deprived of RET kinase lack intestinal neurons and other neurological abnormalities appear, suggesting that functional RET kinase protein products are required during development (Taraviras, S. et al. Development, 1999, 126: 2785-2797). In addition, ethnic studies of patients with Hirschsprung's disease characterized by a lack of normal colonic activity have found a high proportion of patients with familial and sporadic loss of functional RET mutations (Butler Tjaden N. et al. Transl. Res., 2013, 162: 1-15).

Similarly, abnormal RET kinase activity and multiple endocrine neoplasia (MEN 2A and 2B), familial medullary thyroid carcinoma (FMTC), mastoid thyroid carcinoma (PTC), and Hirschsprung's disease (HSCR) (Borello, M. et al. Expert) Opin. Ther. Targets, 2013, 17: 403-419). MEN 2A is a functional domain mutation of extracellular enriched cysteine due to RET, so that it dimerizes by disulfide bond, resulting in constitutive activation of tyrosine kinase activity, resulting in cancer syndrome (Wells Jr, S. J. Clin. Endocrinol. Metab., 2013, 98: 3149-3164). Individuals with this mutation may develop medullary thyroid carcinoma (MTC), parathyroid hyperplasia, and pheochromocytoma. MEN 2B is caused by the Met918Thr mutation of RET, which alters the specificity of tyrosine kinase. MEN 2B is similar to MEN 2A, but no parathyroid hyperplasia occurs, and the lips are also developed; many mucosal ganglia of the tongue and intestine. Chromosomal rearrangement of a constitutively activated chimeric receptor (RET/PTC) caused by a promoter and an NH2-terminal domain or an irrelevant gene (group) linked to the COOH-terminus of RET kinase is considered to be a tumor in PTC Event (Viglietto, G. et al. Oncogene, 1995, 11: 1207-1210). Among all thyroid cancers, PTC accounts for about 80%. These data show that inhibition of RET may be an attractive medical treatment for IBS-related pain and other gastrointestinal disorders, and can be used to treat cancers with constitutive RET kinase activity.

The invention relates to a compound of formula (I):

Wherein: R ¹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, hydroxy, (C ₁ -C ₆ ) Alkoxy, halo(C ₁ -C ₆ )alkoxy, (C ₃ -C ₆ )cycloalkoxy, amine, ((C ₁ -C ₆ )alkyl)amino-, or ((C ₁ -C ₆ )alkyl)((C ₁ -C ₆ )alkyl)amino-; each R ^{2 is} independently selected from the group consisting of halogen, (C ₁ -C ₆ )alkyl, Halogen (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, cyano, hydroxy, (C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkoxy, (C ₃ -C ₆ )cycloalkoxy, amine, ((C ₁ -C ₆ )alkyl)amino-, and ((C ₁ -C ₆ )alkyl) ((C ₁ -C ₆ ) Alkyl)amino-; R ³ is phenyl or 5- or 6-membered heteroaryl, which may be optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halogen, (C ₁ -C ₆ An alkyl group, a halogen (C ₁ -C ₆ )alkyl group, a (C ₃ -C ₆ )cycloalkyl group, a cyano group, a 5- or 6-membered heteroaryl group, -OR ⁴ , and -CONR ⁵ R ⁶ ; Wherein the (C ₁ -C ₆ )alkyl group may be optionally substituted with a cyano group, a hydroxyl group, a (C ₁ -C ₄ ) alkoxy group, a halogen (C ₁ -C ₄ ) alkoxy group, or —NR ⁵ R ⁶ ; And wherein the 5- or 6-membered heteroaryl substituent is Substituted by halogen, (C ₁ -C ₄ )alkyl, or halo(C ₁ -C ₄ )alkyl; R ⁴ is hydrogen, (C ₁ -C ₆ )alkyl, halo (C ₁ -C ₆ An alkyl group, a (C ₃ -C ₆ )cycloalkyl group, or a 4- to 6-membered heterocycloalkyl group; wherein the (C ₁ -C ₆ )alkyl group may optionally be via a cyano group, a hydroxy group, (C ₁ - C ₄ ) alkoxy, halo(C ₁ -C ₄ )alkoxy, or -NR ⁵ R ⁶ substituted; and wherein the (C ₃ -C ₆ )cycloalkyl group may be independently selected by 1 or 2, respectively Substituted from the following substituents: (C ₁ -C ₄ )alkyl, halo(C ₁ -C ₄ )alkyl, hydroxy, hydroxy(C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy And a halogen (C ₁ -C ₄ ) alkoxy group; and wherein the 4- to 6-membered heterocycloalkyl group may be optionally substituted with 1 or 2 substituents each independently selected from the group consisting of: (C ₁ -C) ₄ ) an alkyl group and a halogen (C ₁ -C ₄ ) alkyl group; the R ⁵ and R ⁶ groups are each independently selected from the group consisting of hydrogen, (C ₁ -C ₄ )alkyl, and halogen (C) ₁ -C ₄ )alkyl; or R ⁵ and R ^{6 together} with the nitrogen to which they are attached represent a 5- or 6-membered saturated ring which may optionally comprise another hetero atom selected from the group consisting of oxygen, nitrogen and sulfur, wherein The ring may optionally be halogen, (C ₁ -C ₄ )alkyl, or halogen (C ₁ -C) ₄ ) an alkyl group; and n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof.

The invention also relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable excipient.

The invention also relates to a method of treating intestinal irritation comprising administering to a human in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The invention also relates to a method of treating cancer comprising administering to a human in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The invention also relates to a compound of formula (I) for use in medicine. The invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of intestinal irritation. The invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of cancer.

The invention also relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease mediated by RET. The invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of intestinal irritation. The invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer.

The invention relates to a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

The invention also relates to a compound of formula (II):

Wherein: X is N or CR ¹⁰ ; R ¹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, hydroxy, (C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkoxy, (C ₃ -C ₆ )cycloalkoxy, amine, ((C ₁ -C ₆ )alkyl)amine a base-, or ((C ₁ -C ₆ )alkyl)((C ₁ -C ₆ )alkyl)amino group; each R ^{2 is} independently selected from the group consisting of: halogen, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, cyano, hydroxy, (C ₁ -C ₆ )alkoxy, halogen (C ₁ - C ₆ ) alkoxy, (C ₃ -C ₆ )cycloalkoxy, amine, ((C ₁ -C ₆ )alkyl)amino-, and ((C ₁ -C ₆ )alkyl) ( (C ₁ -C ₆ )alkyl)amino-; R ⁴ is hydrogen, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl Or a 4- to 6-membered heterocycloalkyl; wherein the (C ₁ -C ₆ )alkyl group may optionally be through a cyano group, a hydroxy group, a (C ₁ -C ₄ ) alkoxy group, a halogen (C ₁ -C ₄ Alkoxy, or -NR ⁵ R ⁶ substituted; and wherein the (C ₃ -C ₆ )cycloalkyl group may be substituted by 1 or 2 substituents each independently selected from: (C ₁ -C ₄ ) Alkyl, halo(C ₁ -C ₄ )alkyl, hydroxy, hydroxy (C ₁ -C ₄ An alkyl group, a (C ₁ -C ₄ ) alkoxy group, and a halogen (C ₁ -C ₄ ) alkoxy group; and wherein the 4- to 6-membered heterocycloalkyl group may be independently 1 or 2 independently Substituents selected from the group consisting of: (C ₁ -C ₄ )alkyl and halo(C ₁ -C ₄ )alkyl; R ⁵ and R ⁶ are each independently selected from the group consisting of: hydrogen, ( C ₁ -C ₄ )alkyl, and halo(C ₁ -C ₄ )alkyl; or R ⁵ and R ^{6 together} with the nitrogen to which they are attached represent a 5- or 6-membered saturated ring, which may optionally contain another a hetero atom selected from the group consisting of oxygen, nitrogen and sulfur, wherein the ring may be optionally substituted by halogen, (C ₁ -C ₄ )alkyl, or halo(C ₁ -C ₄ )alkyl; R ⁷ is hydrogen, halogen, Or (C ₁ -C ₄ )alkoxy; R ⁸ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl , cyano, 5- or 6-membered heteroaryl, -OR ⁴ , or -CONR ⁵ R ⁶ ; wherein the (C ₁ -C ₆ )alkyl group may optionally be cyano, hydroxy, (C ₁ -C ₄ Alkoxy, halo(C ₁ -C ₄ )alkoxy, or -NR ⁵ R ⁶ substituted; and wherein the 5- or 6-membered heteroaryl can be halogenated, (C ₁ -C ₄ ) alkane as desired a group or a halogen (C ₁ -C ₄ )alkyl group; R ⁹ is hydrogen, halogen, or halogen ( C ₁ -C ₄ )alkyl; R ¹⁰ is hydrogen, halogen, halo(C ₁ -C ₄ )alkyl, or 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is visible It is required to be substituted by halogen, (C ₁ -C ₄ )alkyl, or halo(C ₁ -C ₄ )alkyl; and n is 0, 1, or 2; however, the limitation is that when X is CR ¹⁰ , R ^7. At least one of R ⁸ , R ⁹ , and R ¹⁰ is hydrogen; or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention relates to a compound of formula (I) or (II), wherein R ¹ is fluoro, chloro, (C ₁ -C ₄ )alkyl, hydroxy, (C ₁ -C ₄ ) Alkoxy, halo(C ₁ -C ₄ )alkoxy, (C ₃ -C ₆ )cycloalkoxy, amine, ((C ₁ -C ₆ )alkyl)amino-, or ((C _1- C ₆ )alkyl)((C ₁ -C ₆ )alkyl)amino-. In another embodiment, the invention relates to a compound of formula (I) or (II), wherein R ¹ is (C ₁ -C ₄ )alkoxy. In a specific embodiment, the invention relates to a compound of formula (I) or (II) wherein R ¹ is ethoxy.

In another embodiment, the invention relates to a compound of formula (I) or (II) wherein n is 1 or 2 and each R ^{2 is} independently halogen. In another embodiment, the invention relates to a compound of formula (I) or (II) wherein n is 1 or 2 and each R ² is fluoro.

In another embodiment, the invention relates to a compound of formula (I), wherein R ³ is phenyl, which may optionally be substituted with from 1 to 3 substituents each independently selected from halogen: (C ₁ - C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, cyano, 5- or 6-membered heteroaryl, -OR ⁴ , and -CONR ⁵ R ⁶ ; wherein the (C ₁ -C ₆ )alkyl group may be optionally subjected to a cyano group, a hydroxyl group, a (C ₁ -C ₄ ) alkoxy group, a halogen (C ₁ -C ₄ ) alkoxy group, or -NR ⁵ R ⁶ Substituting; and wherein the 5- or 6-membered heteroaryl group may be optionally substituted by halogen, (C ₁ -C ₄ )alkyl, or halo(C ₁ -C ₄ )alkyl. In another embodiment, the invention relates to a compound of formula (I), wherein R ³ is phenyl, which may optionally be substituted with from 1 to 3 substituents each independently selected from the group consisting of fluorine, chlorine, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )alkoxy, hydroxy(C ₂ -C ₄ )alkoxy-, (C ₁ - C ₄ ) alkoxy (C ₂ -C ₄ ) alkoxy-, amine (C ₂ -C ₄ ) alkoxy-, ((C ₁ -C ₄ )alkyl)amino group (C ₂ -C ₄ ) alkoxy-, ((C ₁ -C ₄ )alkyl)((C ₁ -C ₄ )alkyl)amino (C ₂ -C ₄ ) alkoxy-, and -CONH ₂ ; (C ₁ -C ₆ )alkyl may optionally be via cyano, hydroxy, (C ₁ -C ₄ )alkoxy, amine, ((C ₁ -C ₄ )alkyl)amino-, or ((C ₁ -C ₄ )alkyl)((C ₁ -C ₄ )alkyl)amino-substituted. In another embodiment, the invention relates to a compound of formula (I), wherein R ³ is phenyl, which may be substituted, if desired, with 1 or 2 substituents each independently selected from: (C ₁ -C ₄ And an alkyl (C ₁ -C ₄ ) alkyl group; wherein the (C ₁ -C ₄ )alkyl group may be substituted with a cyano group or a hydroxy group as needed.

In another embodiment, the invention relates to a compound of formula (I), wherein R ³ is furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, Azolyl, thiazolyl, iso Azyl, isothiazolyl, Diazolyl, thiadiazolyl, pyridyl, anthracene Base Base, pyrimidinyl, or tri a group which may be optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halogen, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, (C ₃ -C ₆ a cycloalkyl group, a cyano group, a 5- or 6-membered heteroaryl group, -OR ⁴ , and -CONR ⁵ R ⁶ ; wherein the (C ₁ -C ₆ )alkyl group may optionally contain a cyano group, a hydroxyl group, (C ₁ -C ₄ ) alkoxy, halo(C ₁ -C ₄ )alkoxy, or -NR ⁵ R ⁶ substituted; and wherein the 5- or 6-membered heteroaryl can be optionally halogenated, (C ₁ - C ₄ ) an alkyl group or a halogen (C ₁ -C ₄ ) alkyl group. In another embodiment, the invention relates to a compound of formula (I), wherein R ³ is furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, Azolyl, thiazolyl, iso Azyl, isothiazolyl, Diazolyl, thiadiazolyl, pyridyl, anthracene Base Base, pyrimidinyl, or tri a group which may be optionally substituted with 1 to 3 substituents each independently selected from the group consisting of fluorine, chlorine, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₄ )alkyl, cyano, C ₁ -C ₄ ) alkoxy, hydroxy(C ₂ -C ₄ )alkoxy-, (C ₁ -C ₄ )alkoxy(C ₂ -C ₄ )alkoxy-,amino group (C ₂ -C ₄ ) alkoxy-, ((C ₁ -C ₄ )alkyl)amino (C ₂ -C ₄ ) alkoxy-, ((C ₁ -C ₄ )alkyl) ((C ₁ - C ₄ )alkyl)amino (C ₂ -C ₄ )alkoxy-, and -CONH ₂ ; wherein the (C ₁ -C ₆ )alkyl group may optionally be cyanyl, hydroxy, (C ₁ -C ₄ Alkoxy, amine, ((C ₁ -C ₄ )alkyl)amino-, or ((C ₁ -C ₄ )alkyl)((C ₁ -C ₄ )alkyl)amino-substituted .

In another embodiment, the invention relates to a compound of formula (I), wherein R ³ is pyridyl, which may optionally be substituted with 1 to 3 substituents each independently selected from the group consisting of fluorine, chlorine, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₄ )alkyl, cyano, (C ₁ -C ₄ )alkoxy, hydroxy(C ₂ -C ₄ )alkoxy-, (C ₁ - C ₄ ) alkoxy (C ₂ -C ₄ ) alkoxy-, amine (C ₂ -C ₄ ) alkoxy-, ((C ₁ -C ₄ )alkyl)amino group (C ₂ -C ₄ ) alkoxy-, ((C ₁ -C ₄ )alkyl)((C ₁ -C ₄ )alkyl)amino (C ₂ -C ₄ ) alkoxy-, and -CONH ₂ ; (C ₁ -C ₆ )alkyl may optionally be via cyano, hydroxy, (C ₁ -C ₄ )alkoxy, amine, ((C ₁ -C ₄ )alkyl)amino-, or ((C ₁ -C ₄ )alkyl)((C ₁ -C ₄ )alkyl)amino-substituted. In another embodiment, the invention relates to a compound of formula (I), wherein R ³ is pyridyl, which may be substituted, if desired, with 1 or 2 substituents each independently selected from: (C ₁ -C ₄ And an alkyl (C ₁ -C ₄ ) alkyl group; wherein the (C ₁ -C ₄ )alkyl group may be substituted with a cyano group or a hydroxy group as needed.

In another embodiment, the invention relates to a compound of formula (I), wherein R ³ is furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, Azolyl, thiazolyl, iso Azyl, isothiazolyl, Diazolyl, thiadiazolyl, pyridyl, anthracene Base Base, pyrimidinyl, or tri A group which may be optionally substituted with a (C ₁ -C ₄ )alkyl group or a halogen (C ₁ -C ₄ )alkyl group as needed. In another embodiment, the invention relates to a compound of formula (I) wherein R ³ is different An oxazolyl group which may optionally be substituted by (C ₁ -C ₄ )alkyl or halo(C ₁ -C ₄ )alkyl.

In another embodiment, the present invention relates to a compound structure of formula (II), wherein R ⁷ is hydrogen or halogen. In a specific embodiment, the present invention relates to a compound structure of formula (II) particular embodiment, wherein R ⁷ is hydrogen or fluorine. In a more specific embodiment, the invention relates to a compound of formula (II) wherein R ⁷ is hydrogen.

In another embodiment, the invention relates to a compound of formula (II), wherein R ⁸ is hydrogen, fluoro, chloro, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₄ )alkyl, Cyano, (C ₁ -C ₄ )alkoxy, hydroxy(C ₂ -C ₄ )alkoxy-, (C ₁ -C ₄ )alkoxy(C ₂ -C ₄ )alkoxy-,amine (C ₂ -C ₄ )alkoxy-, ((C ₁ -C ₄ )alkyl)amino (C ₂ -C ₄ )alkoxy-, ((C ₁ -C ₄ )alkyl) ( (C ₁ -C ₄ )alkyl)amino (C ₂ -C ₄ )alkoxy-, or -CONH ₂ ; wherein the (C ₁ -C ₆ )alkyl group may optionally be cyano, hydroxy, (C ₁ -C ₄ ) alkoxy, amine, ((C ₁ -C ₄ )alkyl)amino-, or ((C ₁ -C ₄ )alkyl)((C ₁ -C ₄ )alkyl) Amino-substituted. In another embodiment, the invention relates to a compound of formula (II), wherein R ⁸ is hydrogen or (C ₁ -C ₆ )alkyl; wherein the (C ₁ -C ₆ )alkyl group may optionally undergo cyanide Base, hydroxy, (C ₁ -C ₄ ) alkoxy, amine, ((C ₁ -C ₄ )alkyl)amino-, or ((C ₁ -C ₄ )alkyl) ((C ₁ - C ₄ )alkyl)amino-substituted. In another embodiment, the invention relates to a compound of formula (II), wherein R ⁸ is (C ₁ -C ₄ )alkyl, which may optionally be via cyano, hydroxy, (C ₁ -C ₄ ) alkane Oxyl, amine, ((C ₁ -C ₄ )alkyl)amino-, or ((C ₁ -C ₄ )alkyl)((C ₁ -C ₄ )alkyl)amino-substituted.

In another embodiment, the invention relates to a compound of formula (II), wherein R ⁹ is halo(C ₁ -C ₄ )alkyl. In a specific embodiment, the present invention relates to a compound structure of formula (II) particular embodiment, wherein R ⁹ is trifluoromethyl.

In another embodiment, the invention relates to a compound of formula (II) wherein X is CR ¹⁰ and R ¹⁰ is hydrogen, halogen, halo(C ₁ -C ₄ )alkyl, furyl, thienyl, Pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, Azolyl, thiazolyl, iso Azyl, isothiazolyl, Diazolyl, thiadiazolyl, pyridyl, anthracene Base Base, pyrimidinyl, or tri a base thereof, wherein the furyl group, thienyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, Azolyl, thiazolyl, iso Azyl, isothiazolyl, Diazolyl, thiadiazolyl, pyridyl, anthracene Base Base, pyrimidinyl, or tri The base may need to be substituted by halogen, (C ₁ -C ₄ )alkyl, or halo(C ₁ -C ₄ )alkyl. In another embodiment, the invention relates to a compound of formula (II) wherein X is CR ¹⁰ and R ¹⁰ is hydrogen, fluoro, chloro, or trifluoromethyl. In a specific embodiment, the invention relates to a compound of formula (II) wherein X is CH. In another specific embodiment, the invention relates to a compound of formula (II) wherein X is N.

In a specific embodiment, the invention relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein: X is CH; R ¹ is (C ₁ -C ₄ )alkoxy; each R ² Each is independently halogen; R ⁷ is hydrogen or halogen; R ⁸ is hydrogen, fluorine, chlorine, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₄ )alkyl, cyano, (C ₁ -C) ₄ ) alkoxy group, hydroxy (C ₂ -C ₄ ) alkoxy group, (C ₁ -C ₄ ) alkoxy group (C ₂ -C ₄ ) alkoxy group, amine group (C ₂ -C ₄ ) Alkoxy-, ((C ₁ -C ₄ )alkyl)amino (C ₂ -C ₄ ) alkoxy-, ((C ₁ -C ₄ )alkyl) ((C ₁ -C ₄ ) alkane Amino (C ₂ -C ₄ )alkoxy-, or -CONH ₂ ; wherein the (C ₁ -C ₆ )alkyl group may optionally be via a cyano group, a hydroxy group, or a (C ₁ -C ₄ ) alkoxy group. , an amine group, ((C ₁ -C ₄ )alkyl)amino-, or ((C ₁ -C ₄ )alkyl)((C ₁ -C ₄ )alkyl)amino-substituted; R ⁹ is Halogen (C ₁ -C ₄ )alkyl; and N is 1 or 2.

In a specific embodiment, the invention relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein: X is N; R ¹ is (C ₁ -C ₄ )alkoxy; each R ² Each is independently halogen; R ⁷ is hydrogen or halogen; R ⁸ is hydrogen, fluorine, chlorine, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₄ )alkyl, cyano, (C ₁ -C) ₄ ) alkoxy group, hydroxy (C ₂ -C ₄ ) alkoxy group, (C ₁ -C ₄ ) alkoxy group (C ₂ -C ₄ ) alkoxy group, amine group (C ₂ -C ₄ ) Alkoxy-, ((C ₁ -C ₄ )alkyl)amino (C ₂ -C ₄ ) alkoxy-, ((C ₁ -C ₄ )alkyl) ((C ₁ -C ₄ ) alkane Amino (C ₂ -C ₄ )alkoxy-, or -CONH ₂ ; wherein the (C ₁ -C ₆ )alkyl group may optionally be via a cyano group, a hydroxy group, or a (C ₁ -C ₄ ) alkoxy group. , an amine group, ((C ₁ -C ₄ )alkyl)amino-, or ((C ₁ -C ₄ )alkyl)((C ₁ -C ₄ )alkyl)amino-substituted; R ⁹ is Halogen (C ₁ -C ₄ )alkyl; and N is 1 or 2.

The invention also relates to a compound, which is illustrated in the experimental section.

Specifically compounds of this invention include: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (6- (2-hydroxypropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide; N- (6-ethoxy-5-(trifluoromethyl)pyridine-3- 2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidamine; 2-(4-( 4- ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (4- (3- hydroxy-2,2-dimethyl-propionic 3-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2 , 3-difluorophenyl) - N - (4- (2- hydroxyethoxy) -3- (trifluoromethyl) phenyl) as acetamide; 2- (4- (5-ethoxy - 6--oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (4- (3- hydroxy-2,2-dimethylpropyl) -3- ( Trifluoromethyl)phenyl)acetamidamine; 2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-3-fluorophenyl)- N- (4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide; N- (4-cyano-3-(trifluoromethyl) Phenyl)-2-(4-(4-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-3-fluorophenyl)acetamidamine; 2-( 4-(5-ethoxy-6-sideoxy-1 6-dihydropyridin-3-yl) -2,6-difluorophenyl) - N - (4- (2- hydroxyethoxy) -3- (trifluoromethyl) phenyl) acetyl amine N- (4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl) -2-fluorophenyl)acetamidamine; N- (6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-2-( 4-(4-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidamine; 2-(4-(5-ethoxy)- 6--oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (4- methyl -1 H - imidazol-1-yl) -5- ( Trifluoromethyl)phenyl)acetamide; N- (6-(2-cyanopropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-( 5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidamine; 2-(4-(5-ethoxy-6-side) oxy-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (4- (2- hydroxyethoxy) -3- (trifluoromethyl) phenyl) acetyl Amine; N- (6-(cyanomethyl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-o-oxy-1,6 -dihydropyridin-3-yl)-2-fluorophenyl)acetamide; N- (6-(1-cyanoethyl)-5-(trifluoromethyl)pyridin-3-yl)-2 -(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridine) -3-yl)-2-fluorophenyl)acetamide; N- (4-chloro-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-side) Oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide; N- (4-((dimethylamino)methyl)-3-(trifluoromethyl) Phenyl)-2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide; N- (3) ,4-dichlorophenyl)-2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide; 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (5- (1,1,1- Trifluoro-2-methylpropan-2-yl)iso Oxadiazol-3-yl) acetyl amine; 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamide; 2-(4-(5-ethoxy-6-yloxy-1,6-di) hydrogen pyridin-3-yl) -2-fluorophenyl) - N - (4 - ( (4- ethylpiperazin -1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide; N- (2,5-difluorophenyl)-2-(4-(5-ethoxy-6) -Sideoxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidamine; 4-(2-(4-(5-ethoxy-6-yloxy-1) ,6-dihydropyridin-3-yl)-2-fluorophenyl)ethylamino)-2-(trifluoromethyl)benzamide; N- (2,4-difluoro-5-( Trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide; N- (3,5-bis(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2 - fluorophenyl) as acetamide; 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - ( 2-fluoro-5-(trifluoromethyl)phenyl)acetamidamine; 2-(4-(4-ethoxy-6-oxooxy-1,6-dihydropyridin-3-yl)- 2-fluorophenyl) - N - (3- (1,1,1- trifluoro-2-methylpropan-2-yl) iso Oxadiazol-5-yl) acetyl amine, 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3-(1,1,1-trifluoro-2-methylpropan-2-yl)iso Oxadiazol-5-yl) acetyl amine; 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3-(5-methyl-1,3,4- Diazol-2-yl)-5-(trifluoromethyl)phenyl)acetamidamine; 2-(4-(4-ethoxy-6-o-oxy-1,6-dihydropyridine-3 - yl) -2-fluorophenyl) - N - (5- (1,1,1- trifluoro-2-methylpropan-2-yl) iso Oxadiazol-3-yl) acetyl amine; 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (6-(1-hydroxy-2-methylpropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamidamine; 2-(4-(4-ethoxy-6) --oxo-1,6-dihydropyridin-3-yl) -3-fluorophenyl) - N - (4- (3- hydroxy-2,2-dimethylpropyl) -3- (C Fluoromethyl)phenyl)acetamidine; 2-(4-(4-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl) -N -(3-(trifluoromethyl)phenyl)acetamidamine; 2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2- fluorophenyl) - N - (3- (4- methyl -1 H - pyrazol-1-yl) -5- (trifluoromethyl) phenyl) as acetamide; 2- (4- (5- ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (3- methyl -1 H - pyrazol-1-yl -5-(Trifluoromethyl)phenyl)acetamidamine; N- (3-(1 H -pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-2-(4) -(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidamine; 2-(4-(4-ethoxy-6) --oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (6- (1,1,1- trifluoro-2-methylpropan-2-yl) Pyridin-3-yl)acetamide; N- (4-cyano-3-(trifluoromethyl)phenyl)-2-(4-( 4-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidamine; 2-(4-(5-ethoxy-6-side) oxy-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (2- morpholino-ethoxy) -5- (trifluoromethyl) phenyl) as acetamide; 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (1 , 1,1-trifluoro-2-methylpropan-2-yl)iso Oxadiazol-5-yl) acetyl amine; 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (1-methyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1 H -pyrazol-5-yl)acetamidamine; 2-(4-(5 - ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (1,1,1- trifluoro-2-methyl Propane-2-yl)-1 H -pyrazol-5-yl)acetamide; N- (4-(2,2-difluoro-3-hydroxypropyl)-3-(trifluoromethyl)benzene 2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide; N- (3-( 2 H -tetrazol-5-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridine-3 -yl)-2-fluorophenyl)acetamide; 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl ) - N - (3- (1- methyl -1 H - pyrazol-4-yl) -5- (trifluoromethyl) phenyl) as acetamide; and N - (3- (2- (two Methylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridine-3- (2-fluorophenyl)acetamidamine; or a pharmaceutically acceptable salt thereof.

It is well understood by those skilled in the relevant art that the compounds of the present invention may have different names when different naming softwares are employed.

The invention also relates to a compound of formula (I) or (II), or any of its exemplified compounds, or a pharmaceutically acceptable salt thereof, for use in medicine. Specifically, for the treatment of RET-mediated diseases: intestinal irritation (IBS), including diarrhea, constipation or alternating fecal type; functional flatulence, functional constipation, functional diarrhea, unclear functionality Intestinal lesions, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disease, functional gastric and duodenal lesions, functional anorectal pain, inflammatory bowel disease; proliferative diseases such as non-small cell lung cancer , hepatocellular carcinoma, colorectal cancer, medullary thyroid carcinoma, follicular thyroid cancer, thyroid undifferentiated carcinoma, mastoid thyroid cancer, brain tumor, peritoneal cancer, solid tumor, other lung cancer, head and neck cancer, Glioma, neuroblastoma, Von Hippel-Lindau Syndrome, and kidney, breast, fallopian tube, ovarian, transitional epithelial, prostate, esophagus and gastroesophage Intersection of cancer, biliary and adenocarcinoma. In particular, the invention relates to a compound of formula (I) or (II) or any of its exemplified compounds, or a pharmaceutically acceptable salt thereof, for use in the treatment of intestinal irritation (IBS), including Diarrhea, constipation or alternating fecal type; functional flatulence, functional constipation, functional diarrhea, unclear functional bowel disease, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disease, functional Gastric and duodenal lesions, functional anorectal pain, inflammatory bowel disease, non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, medullary thyroid carcinoma, follicular thyroid cancer, anaplastic thyroid cancer, Mastoid thyroid cancer, brain tumors, peritoneal cancer, solid tumors, other lung cancers, head and neck cancer, gliomas, neuroblastoma, Von Hippel-Lindau Syndrome, and kidney tumors, Breast cancer, fallopian tube cancer, ovarian cancer, transitional epithelial cell carcinoma, prostate cancer, cancer of the esophagus and gastroesophageal junction, biliary and adenocarcinoma.

The invention also relates to a compound of formula (I) or (II), or any of its exemplified compounds, or a pharmaceutically acceptable salt thereof, for use as a medicament. In another embodiment, the invention relates to the use of a compound of the invention for the manufacture of a medicament for the treatment of a RET mediated disease. The invention also relates to a compound of formula (I) or (II), or any of its exemplified compounds, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of intestinal irritation. The invention also relates to a compound of formula (I) or (II), or any of its exemplified compounds, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of cancer.

The invention also relates to the use of a compound of formula (I) or (II) or any of its exemplified compounds for medical purposes. The invention further encompasses the use of a compound of the invention as a medically active substance, in particular for the treatment of RET mediated diseases. The invention also relates to the use of a compound of formula (I) or (II) or any of its exemplified compounds for the treatment of intestinal irritation. The invention also relates to the use of a compound of formula (I) or (II) or any of its exemplified compounds for the treatment of cancer.

Based on the medically potential use of the compounds of formula (I), the salts of the compounds of formula (I) are preferably pharmaceutically acceptable. Suitable pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci. (1977) 66, pp 1-19. The term "sodium pharmaceutically acceptable salts" as used herein means a non-toxic salt of a compound of the invention. Salts of the disclosed compounds comprising a basic amine or other basic functional group can be made by any suitable method known in the art, including the use of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Or use organic acids such as: acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid; : glucuronic acid or galacturonic acid; α-hydroxy acids such as: citric acid or tartaric acid; amino acids such as aspartic acid or glutamic acid; aromatic acids such as benzoic acid or cinnamic acid; The free base is treated with an acid such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, or the like. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, hydrogen sulfates, sulfites, bisulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanes. Acid salt, octanoate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propionate, oxalate, malonate, succinate, suberate, bismuth Acid salt, fumarate, maleate, butyne-1,4-diate, hexyne-1,6-diate, benzoate, chlorobenzoate, methylbenzene Acid salt, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, decanoate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, Lactate, γ-hydroxybutyrate, glycolate, tartrate, mandelate, and sulfonate, such as: xylene sulfonate, methanesulfonate, propane sulfonate, naphthalene-1-sulfonic acid Salt and naphthalene-2-sulfonate.

Salts of the disclosed compounds comprising a carboxylic acid or other acidic functional group can be prepared using a suitable base. Such pharmaceutically acceptable salts can be prepared using bases which provide pharmaceutically acceptable cations, including alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts. And ammonium salts, and salts prepared from physiologically acceptable organic bases, such as: trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N , N '-diphenylmethylethylenediamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tris-(2-hydroxyethyl)amine, procaine, diphenyl Piperidine, dehydroabietic amine, N , N '-didehydroabisamine, glucosamine, N -methylglucamine, trimethylpyridine, choline, quinine, quinoline, and basic amine Base acids, such as: amine acid and arginine.

Other pharmaceutically unacceptable salts may be suitable for the preparation of the compounds of the invention, and such salts are considered to be another aspect of the invention. Such salts, such as trifluoroacetate, although not themselves pharmaceutically acceptable, may be suitable for the preparation of salts suitable for use as intermediates. The compounds of the invention and their pharmaceutically acceptable salts.

If a compound of the invention comprising a basic amine or other basic functional group is isolated as a salt form, the corresponding free base form of the compound can be prepared by any suitable method known in the art, including the use of an inorganic or organic base (suitable This salt form is treated with an inorganic or organic base having a free KK _a higher than the free base type of the compound. Similarly, if a compound of the invention comprising a carboxylic acid or other acidic functional group is isolated as a salt form, the corresponding free acid form of the compound can be prepared by any suitable method known in the art, including the use of inorganic or organic acids ( pK _a less than desirable to use the compound in a free acid form of inorganic or organic acids) treating the salt form.

The term "compound of formula (I)" or "compound of formula (I)" as used herein refers to one or more compounds according to formula (I). The compounds of formula (I) may be in solid or liquid form. When it is in a solid state, it may be crystalline or amorphous, or a mixture thereof. It is well understood by those skilled in the relevant art that the pharmaceutically acceptable solvate can be formed from crystalline or amorphous compounds. In crystalline solvates, solvent molecules enter the crystal lattice during crystallization. The solvate may be involved in a non-aqueous solvent such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or it may involve water entering the crystal lattice as a solvent. A solvate in which water is a solvent that enters the crystal lattice is often referred to as a "hydrate." Hydrates include stoichiometric hydrates and compositions comprising various amounts of water. The invention includes all such solvates.

It will also be apparent to those skilled in the relevant art that certain of the compounds of the present invention may be in crystalline form, including various different solvates thereof, and may be polymorphic (i.e., capable of undergoing different crystalline structures). These different crystal structures are often referred to as "polymorphs". The invention includes such polytypes. Polymorphs have the same chemical composition, but differ in the stacking, geometric alignment, and other properties of the crystalline solid state. Therefore, polymorphs may have different physical properties such as shape, density, hardness, deformability, stability, and solubility. Polymorphs usually have different melting points, IR spectra, and X-ray diffraction patterns, which can be used for discrimination. People familiar with this related skill can understand, for example, change Alternatively, the reaction conditions or reagents used in the manufacture of the compounds are adjusted to produce different polytypes. For example, changing the temperature, pressure or solvent may result in a polytype. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.

The compound of formula (I) or (II) or a salt thereof may be in a stereoisomeric form (for example, it contains one or more asymmetric carbon atoms). Individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are included within the scope of the invention. The scope of the invention includes mixtures of stereoisomers and purified enantiomers or enriched enantiomeric/diastereomeric mixtures.

Similarly, it is understood that the compound of the formula (I) or (II) or a salt thereof may be a tautomeric form different from the chemical formula, and the like is also included in the scope of the present invention. For example, although the compounds of formula (I) and (II) are shown to comprise a pyridin-2-one moiety, corresponding 2-hydroxypyridine tautomers are also included within the scope of the invention. It is understood that the invention includes all combinations and sub-sets of the specific groups defined above.

It is well understood by those skilled in the relevant art that certain protected derivatives of a compound of formula (I) or (II) which may be prepared before or after the final removal of the protecting group step are not necessarily pharmacologically active, but in some instances, It can be administered orally or parenterally and then metabolized in the body to form a pharmacologically active compound of the invention. These derivatives are therefore referred to as "prodrugs". In addition, certain of the compounds of the invention may be used as prodrugs of other compounds of the invention. All protected derivatives and prodrugs of the compounds of the invention are included within the scope of the invention.

Examples of suitable prodrugs of the compounds of the invention are described in "Drugs of Today, Vol. 19, No. 9, 1983, pp 499-538" and "Topics in Chemistry", Chapter 31, pp 306-316", and H. Bundgaard, Elsevier, "Design of Prodrugs", 1985, Chapter 1. It will also be apparent to those skilled in the relevant art that when appropriate functional groups are present in the compounds of the invention, such suitable functional groups may, for example, be found in certain portions of H. Bundgaard's "Design of Prodrugs". Group (familiar with this The off-tech is called the "pre-partial group"). Preferred "pre-partial groups" of the compounds of the invention include: esters, carbonates, half esters, phosphates, nitroesters, sulfates, hydrazines, guanamines, amines of the compounds of formula (I) or (II) Formate, azo-, phosphoniumamine, glycosides, ethers, acetals and deketone derivatives.

A compound of the invention administered as a prodrug may be subjected to one or more of the following treatments: (a) the time at which the modified compound begins to act in vivo; (b) the time effect of the modified compound in vivo to maintain action (c) the transport or distribution of the modified compound in vivo; (d) the solubility of the modified compound in vivo; and (e) overcoming the side effects or other difficulties of the compound.

The invention also includes compounds labeled with isotopes which are identical to the compounds of formula (I), but wherein one or more of the atoms are replaced by another atom having an atomic weight or mass number different from its natural atomic weight or mass number. Examples of isotopes which may enter the compounds of the invention and their pharmaceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as: ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I, and ¹²⁵ I.

Compounds of the invention and pharmaceutically acceptable salts of such compounds comprising the above isotopes and/or other isotopes of other atoms are within the scope of the invention. The compounds of the invention labeled with isotopes (for example, those in which a radioisotope such as ³ H or ¹⁴ C is incorporated) are suitable for use in drug and/or matrix analysis. Deuterated (ie ³ H) and carbon-14 (ie ¹⁴ C) isotopes are particularly suitable for ease of manufacture and testing. ^{The 11} C and ¹⁸ F isotopes are particularly suitable for PET (positive sonographic computed tomography), and the ¹²⁵ I isotope is particularly suitable for SPECT (single photon emission computed tomography), both for brain imaging. In addition, substitution with heavier isotopes such as hydrazine (ie, ² H) may provide certain medical benefits by increasing metabolic stability, such as prolonging in vivo half-life or reducing dosage requirements, and thus is more suitable for certain environments. The compound of formula (I) labeled with an isotope can generally be prepared by replacing the unlabeled isotope with an agent of a readily available labeled isotope according to the method disclosed in the reaction schemes and/or examples below.

definition

The terms used are within their acceptable definitions.

The following definitions are only used to clarify the terms defined, but are not limited.

The term "alkyl" as used herein denotes a saturated straight or branched hydrocarbon moiety. The term "(C ₁ -C ₆ )alkyl" refers to an alkyl moiety containing from 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, t-butyl, pentyl and hexyl.

When the term "alkyl" is used in combination with other substituents, such as "halo(C ₁ -C ₄ )alkyl" or "hydroxy(C ₁ -C ₄ )alkyl", the term "alkyl" includes A divalent straight or branched chain hydrocarbon group in which an alkyl moiety is utilized as an attachment point. The term "halo(C ₁ -C ₄ )alkyl" means having one or more than one or more carbon atoms of the alkyl moiety of a straight or branched carbon group containing from 1 to 4 carbon atoms. A plurality of groups of halogen atoms which may be the same or different. Examples of "halo(C ₁ -C ₄ )alkyl" suitable for use in the present invention include, but are not limited to: -CF ₃ (trifluoromethyl), -CCl ₃ (trichloromethyl), 1,1-di Fluoroethyl, 2,2,2-trifluoroethyl, and hexafluoroisopropyl. Examples of "hydroxy(C ₁ -C ₄ )alkyl" suitable for use in the present invention include, but are not limited to, hydroxymethyl, hydroxyethyl, and hydroxyisopropyl.

"Alkoxy" refers to a group comprising an alkyl group as defined above, bonded with an oxygen linking atom. The term "(C ₁ -C ₄₎ alkoxy" refers to the use of an oxygen atom linked to at least one attachment of up to four carbon atoms, straight-chain or branched hydrocarbon radical of. Examples of "(C ₁ -C ₄ )alkoxy" suitable for use in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, second Butoxy, isobutoxy, and third butoxy.

When the term "alkoxy" is used in combination with other substituents, such as: "halo(C ₁ -C ₆ )alkoxy", "hydroxy(C ₂ -C ₄ )alkoxy", or "(C ₁ -C ₄ ) alkoxy (C ₂ -C ₄ )alkoxy", the term "alkoxy" is intended to include a divalent straight or branched chain hydrocarbon group in which the alkyl moiety is attached using an oxygen linking atom Group. The term "halo(C ₁ -C ₆ )alkoxy" refers to having at least one up to 6 carbon atoms attached to an oxygen linking atom and attaching one or more of the same on one or more of the carbon atoms. Or a straight or branched chain hydrocarbon group of a different halogen atom. Examples of "halo(C ₁ -C ₆ )alkoxy" suitable for use in the present invention include, but are not limited to: -OCHF ₂ (difluoromethoxy), -OCF ₃ (trifluoromethoxy), and - OCH(CF ₃ ) ₂ (hexafluoroisopropoxy). Examples of "hydroxy(C ₂ -C ₄ )alkoxy" suitable for use in the present invention include, but are not limited to, 2-hydroxyethoxy and 2-hydroxyisopropoxy. Examples of "(C ₁ -C ₄ )alkoxy(C ₂ -C ₄ )alkoxy" suitable for use in the present invention include, but are not limited to, 2-methoxyethoxy, 2-ethoxyB. Oxyl, 2-isopropoxyethoxy, 2-methoxyisopropoxy, and 2-ethoxyisopropoxy.

The term "cycloalkyl" as used herein, refers to a non-aromatic saturated cyclic hydrocarbon ring containing the specified number of carbon atoms. The term "(C ₃ -C ₆ )cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring having from 3 to 6 ring carbon atoms. Examples of "(C ₃ -C ₆ )cycloalkyl" suitable for use in the present invention include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term "cycloalkyloxy-" as used herein, refers to a group containing a cycloalkyl group as defined above, which is attached by an oxygen-bonding atom. Examples of "(C ₃ -C ₈ )cycloalkyloxy-" suitable for use in the present invention include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy .

As used herein, "4- to 6-membered heterocycloalkyl" refers to a radical or moiety that contains a saturated or partially unsaturated non-aromatic monovalent monocyclic group of 4, 5, or 6 ring atoms. A group comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen. Examples of 4- to 6-membered heterocycloalkyl groups suitable for use in the present invention include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolyl, pyrazolinyl , imidazolidinyl, imidazolinyl, Oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolyl, piperidinyl, piperidin , morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropiperidyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3 - oxathiolane, 1,3-oxathiolanyl, 1,3-dithiacyclohexane, 1,4-oxathiolanyl, 1,4-oxo Heterocyclohexane group and 1,4-dithiacyclohexane group.

As used herein, "5- or 6-membered heteroaryl" represents a group or partial group of a non-aromatic monovalent monocyclic group containing 5 or 6 ring atoms, which includes at least one carbon atom and 1 to Four heteroatoms independently selected from nitrogen, oxygen and sulfur. The 5-membered heteroaryl group selected comprises a nitrogen, oxygen or sulfur ring heteroatom and, if desired, another 1, 2 or 3 nitrogen ring atoms. The 6-membered heteroaryl group selected contains 1, 2, or 3 nitrogen ring heteroatoms. Examples of 5- or 6-membered heteroaryl groups suitable for use in the present invention include, but are not limited to, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, Azolyl, thiazolyl, iso Azyl, isothiazolyl, Diazolyl, thiadiazolyl, pyridyl, anthracene Base Base, pyrimidinyl, and base.

The terms "halogen" and "halo" represent chloro, fluoro, bromo, or iodo substituents. "Hydroxy" refers to the group -OH. The term "cyano" as used herein refers to the group -CN.

The term "optionally substituted" as used herein means that the group (eg, alkyl, cycloalkyl, phenyl, or heteroaryl) may be unsubstituted, or the group may be designated by one or more Substituent (group) substitution. If the groups may be selected from a number of alternative groups, the groups may be the same or different.

The term "separately independent" means that more than one substituent is selected from a number of possible substituents which may be the same or different. The various definitions of the various groups and substituents of formula (I) or (II) provided herein are specifically described individually in the various compound species disclosed herein, and in groups of one or more compound species. The scope of the invention includes any combination of such groups and substituent definitions.

"Pharmaceutically acceptable" means a compound that is suitable for contact with human and animal tissues in the full medical field and that does not exhibit excessive toxicity, irritation or other problems or complications, and which has a reasonable benefit/hazard ratio. , materials, compositions and dosage forms.

The term "pharmaceutically acceptable salts" as used herein refers to salts which retain the desired activity of the subject compound and which have the least undesirable toxic effects. These pharmaceutically acceptable The salts may be prepared in situ during the final isolation and purification of the compound, or otherwise separately from the appropriate base or acid by the purified compound in its free acid form or free base form.

Pharmaceutical composition

The present invention further provides a pharmaceutical composition (also referred to as a pharmaceutical formulation) comprising a compound of the formula (I) or (II) or a pharmaceutically acceptable salt thereof, and one or more excipients (medicine related art) It is called a carrier and/or a diluent). By excipient is pharmaceutically acceptable, it means that it is compatible with the other ingredients of the formulation and is not deleterious to the recipient (i.e., the patient).

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, slip agents, granulating agents, coating agents, wetting agents, Solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, Stabilizers, surfactants and buffers. It will be appreciated by those skilled in the relevant art that certain pharmaceutically acceptable excipients may have more than one function and may provide an alternative function depending on the amount of excipients in the formulation and other inclusions in the formulation. Depending on the ingredients.

Those skilled in the art will have the knowledge and ability of the art to select the appropriate amount of pharmaceutically acceptable excipients suitable for use in the present invention. In addition, many of the pharmaceutically acceptable excipients may be available to those skilled in the art and may be suitable for the selection of suitable pharmaceutically acceptable excipients. Examples thereof include "Remington's Pharmaceutical Sciences (Mack Publishing Company)", "The Handbook of Pharmaceutical Additives" (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients. (the American Pharmaceutical Association and the Pharmaceutical Press).

The pharmaceutical compositions of the present invention are prepared using techniques and methods known in the art. Some of the techniques used in related techniques are described in Reed's Medicine (Remington's Pharmaceutical Sciences) (Mack Publishing Company).

According to another aspect of the present invention, there is provided a process for the preparation of a pharmaceutical composition comprising mixing (or blending) a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, with at least one excipient.

The pharmaceutical composition can be in unit dosage form containing a predetermined amount of active ingredient per unit dosage. These units may contain a therapeutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a portion of a therapeutically effective dose, to administer a multiple unit dosage form at a specified time point. The medically effective dose required. Preferred unit dosage formulations are those which comprise a daily or small dose as described above or a suitable proportion thereof. In addition, such pharmaceutical compositions can be prepared by conventional methods known in the art.

The pharmaceutical composition can be administered in any suitable manner, for example, orally (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal, or parenteral (including subcutaneous, Intramuscular, intravenous or intradermal) pathways. These compositions may be prepared by any method known in the art of pharmacy, for example, by combining the active ingredient with excipients (groups).

When used for oral administration, the pharmaceutical composition may be in a separate unit, such as: a tablet or capsule, a powder or a granule, a solution or suspension in an aqueous or non-aqueous liquid, an edible foaming agent or a foaming agent. , oil-in-water liquid emulsion or oil-in-water liquid emulsion. The compound of the present invention or a salt thereof or the pharmaceutical composition of the present invention can also be incorporated into a confectionery, a powder tablet and/or a tongue tablet formulation as a "quick dissolution" pharmaceutical administration.

For example, when administered orally in the form of a lozenge or capsule, the active pharmaceutical ingredient can be combined with an inert, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Powders or granules are prepared by milling the compound to a suitable fine particle size and combining with a likewise ground pharmaceutical carrier such as an edible carbohydrate such as starch or mannitol. Flavoring, dispersing, and coloring agents may also be included.

The capsule process is a powder mixture prepared as described above and filled into a shaped gelatin or non-gelatin shell. A slip aid and a lubricant (eg, colloidal vermiculite, talc, magnesium stearate, calcium stearate, solid polyethylene glycol) may be added to the powder mixture and then filled. A disintegrant or a dissolving agent (such as agar, calcium carbonate or sodium carbonate) may also be added to improve the availability of the medicine when the capsule is consumed.

Further, a binder, a lubricant, a disintegrant, and a coloring agent may be added to the mixture as needed or necessary. Suitable binders include starch, gelatin, natural sugars (eg glucose or beta-lactose), corn sweeteners, natural and synthetic gums such as acacia, tragacanth, sodium alginate, carboxymethylcellulose. , polyethylene glycol, wax, and so on. Lubricants used in such dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, but are not limited to, starch, methyl cellulose, Chinese cabbage, bentonite, Sanxian gum, and the like.

The tableting method is, for example, preparing a powder mixture, granulating or dicing, adding a lubricant and a disintegrating agent, and pressing into an ingot. The powder mixture is prepared by mixing the compound, if necessary, using a diluent or a substrate as described above, and optionally using a binding agent such as carboxymethyl cellulose, and alginate, gelatin, or polyvinylpyrrolidone, and delaying. A dissolving agent (eg, paraffin), a resorption enhancer (eg, a quaternary salt), and/or an absorbent (eg, bentonite, kaolin, or dicalcium phosphate). The granulation of the powder mixture is humidified using a binder such as a syrup, starch paste, gum arabic, or a solution of cellulose or polymeric material, and then pressurized through a screen. In addition to the granulation method, the powder mixture can be replaced by a tablet press to produce an incompletely formed block which breaks into granules. Stearic acid, stearate, talc or mineral oil may be added to the granules for lubrication to prevent sticking to the mold forming the tablet. The lubricated mixture is then pressed into an ingot. The compounds or salts of the present invention may also be combined with a free-flowing inert carrier for direct compression into tablets without the need for granulation or dicing steps. An opaque, light-shielding protective coating is provided, which is coated with a sealed shellac, icing, Or a polymeric material, and a polishing coating of wax. Dyestuffs can be added to these coatings to distinguish between different doses.

Oral solutions (e.g., solutions, syrups, and elixirs) can be presented in unit dosage form, and may contain a predetermined amount of active ingredient in the specified amount. The syrup is prepared by dissolving the compound of the present invention or a salt thereof in an appropriately flavored aqueous solution, and the elixirs are prepared using a non-toxic alcohol-based vehicle. Suspension formulation is such that the compound or salt of the invention is dispersed in a non-toxic vehicle. Solvents and emulsifiers (such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether), preservatives, flavor additives (such as peppermint oil), natural sweeteners, saccharin, Or other artificial sweeteners, and so on.

If appropriate, the dosage unit formulation for oral administration can be microencapsulated. The formulation may also, for example, be coated or embedded in a polymer, wax, or the like to provide extended or sustained release.

In the present invention, tablets and capsules are more suitable for delivery of pharmaceutical compositions.

The term "treating" as used herein refers to alleviating a particular condition, eliminating or reducing one or more symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying the recurrence of the condition for a patient or individual who has suffered or is diagnosed in the past.

The invention provides a method for treating a mammal (especially a human) suffering from the following diseases: intestinal irritation (IBS), including diarrhea type, constipation type or alternating fecal type; functional flatulence, functional constipation, functional diarrhea Unclear functional intestinal lesions, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal diseases, functional gastric and duodenal lesions, functional anorectal pain, inflammatory bowel disease; proliferative diseases, Such as: non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, medullary thyroid carcinoma, follicular thyroid cancer, thyroid undifferentiated carcinoma, mastoid thyroid cancer, brain tumor, peritoneal cancer, solid tumor, other lung cancer , head and neck cancer, glioma, neuroblastoma, Von Hippel-Lindau Syndrome, and kidney, breast, fallopian tube, ovarian, transitional epithelial cancer, Prostate cancer, cancer of the esophagus and the gastroesophageal junction, biliary and adenocarcinoma, or a combination thereof. Such treatments include the step of administering to a mammal, in particular a human, a therapeutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. The method of treatment also includes the step of administering to the mammal, in particular a human, a therapeutically effective amount of a composition comprising a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof.

The term "effective amount" as used herein means the amount of a drug or agent used by a researcher or clinician to induce a biological or medical response to a tissue, system, animal or human being studied.

The term "medically effective amount" means any amount which, when compared to a corresponding individual who does not receive the same amount, can improve the treatment, healing, prevention or alleviation of the disease, pathology or side effect or reduce the rate of deterioration of the disease or condition. Also included within the scope of the term is an amount effective to enhance normal physiological function. For medical use, a medically effective amount of a compound of formula (I) or (II) and a salt thereof can be administered as a starting material. Further, the active ingredient can be formulated into a pharmaceutical composition. While it is possible to administer a therapeutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof in the original material, it is usually administered as a pharmaceutical composition or formulation of the active ingredient.

The correct medically effective amount of a compound of the invention or a salt thereof will be determined by a number of factors including, but not limited to, the age and weight of the individual (patient) being treated, the actual lesion to be treated and its severity, the pharmaceutical formulation/ The nature of the composition, and the route of administration, and ultimately will be determined by the participating physician or veterinarian. In general, the compound of the formula (I) or (II) or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 0.1 to 100 mg/kg of the body weight of the recipient (patient, mammal) per day, more usually in the range of 0.1 to 10 mg per day. /kg body weight. An acceptable daily dose is from about 0.1 to about 1000 mg/day, and preferably from about 1 to about 100 mg/day. This amount can be administered in a single dose per day or multiple times (e.g., 2, 3, 4, 5 or more times) per day to achieve the same total daily dose. The effective amount of the salt can be converted by the effective amount of the compound of formula (I) or (II) itself. Similar agent The amount should be suitable for the treatment of other conditions than those mentioned herein. Often, people who are familiar with medical or pharmaceutical technology can easily determine the appropriate dosage.

The compounds of the invention may be used alone or in combination with one or more other medical agents. The invention therefore provides a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more other medical agents. These combinations may be presented individually (wherein each active is in a separate composition) or the active is in a combined composition.

The present compound can be administered in combination or co-administered with other medical agents, particularly agents which enhance the activity or accumulation time of the compound. Combination therapies according to the invention include administration of at least one compound of the invention and the use of at least one other method of treatment. In a specific embodiment, the combination therapy according to the invention comprises administering at least one compound of the invention and a surgical treatment. In a specific embodiment, the combination therapy according to the invention comprises administering at least one compound of the invention with radiation therapy. In a specific embodiment, the combination therapy according to the invention comprises administering at least one compound of the invention and at least one supportive care agent (eg, at least one antiemetic agent). In a specific embodiment, the combination therapy according to the invention comprises administering at least one compound of the invention and at least one other chemotherapeutic agent. In a specific embodiment, the invention comprises administering at least one compound of the invention and at least one anti-tumor agent. In still another specific embodiment, in the medical method encompassed by the present invention, the RET inhibitor disclosed herein does not necessarily have active or significant activity per se, but when combined with another therapy that is not necessarily active as a separate therapy, The combination will provide the applicable medical results.

The term "co-administered" and its derivatives, as used herein, refers to the simultaneous administration or in any order in which the RET inhibiting compounds and other active ingredients or groups of ingredients described herein are administered, and in particular, they are known to apply. For the treatment of cancer, including chemotherapy and radiation treatment. The term "other active ingredient or group of ingredients" as used herein includes a compound or a medical agent that is known or has been shown to have beneficial properties when administered to a patient in need of treatment for cancer. Preferably, if the drugs are not administered at the same time, the compounds are administered at a very similar time to each other. In addition, whether the compounds are the same It is not important to administer the dosage form. For example, one of the compounds may be administered topically and the other compound may be administered orally.

Generally, any anti-tumor agent that is active against a therapeutically susceptible tumor can be co-administered for the treatment of a particular cancer of the invention. Examples of such agents can be found in VP Devita and S. Hellman, "Cancer Principles and Practice of Oncology," 6th Edition (February 15, 2001), publisher Lippincott Williams & Wilkins Publishers. The skilled artisan understands that a combination of agents that can be judged according to the characteristics of the drug and the cancer involved. Typical antitumor agents suitable for use in the present invention include, but are not limited to, anti-microtubule agents such as diterpenes and Vinca alkaloids; palladium coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkyl sulfonates, nitrosoureas, and Antibiotic agents, such as: anthracyclins, actinomycin and bleomycin; topoisomerase II inhibitors such as epipodophyllotoxin; antimetabolites such as purines and pyrimidines And antifolate compounds; topoisomerase I inhibitors, such as: camptothecin; hormones and hormone analogues; DNA methyltransferase inhibitors, such as: azacitidine and decitabine (decitabine); signal transduction pathway inhibitor; non-receptor tyrosine kinase angiogenesis inhibitor; immunotherapeutic agent; pro-apoptotic agent; and cell cycle signal transduction inhibitor.

In general, any chemotherapeutic agent that is active against the susceptible tumor being treated can be used in combination with a compound of the invention, provided that the particular agent is clinically compatible with therapies using the compounds of the invention. Typical anti-tumor agents suitable for use in the present invention include, but are not limited to, alkylating agents, antimetabolites, anti-tumor antibiotics, anti-mitotic agents, nucleotide analogs, topoisomerase I and II inhibitors, hormones And hormone analogues; retinoids, histone deacetylase inhibitors; signal transduction pathway inhibitors, including inhibitors of cell growth or growth factor function, angiogenesis inhibitors, and serine/threonine or Other kinase inhibitors; cyclin-dependent kinase inhibitors; antisense therapies and immunotherapeutics, including monoclonal antibodies, vaccines or other biologics Agent.

Nucleotide analogs are compounds in which the DNA can be converted to cytosine by conversion to a deoxynucleotide triphosphate and into replication. DNA methyltransferase is covalently bonded to the modified base, causing enzyme inactivation and reducing DNA methylation. Examples of nucleotide analogs include azacitidine and decitabine, which are useful in the treatment of myelodysplastic lesions. Histone deacetylase (HDAC) inhibitors include: vorinostat, which is used to treat cutaneous T-cell lymphoma. HDAC modifies chromatin by deacetylation of histones. In addition, it has a variety of different receptors, including many transcription factors and signal transduction molecules. Other HDAC inhibitors are still under development.

Signal transduction pathway inhibitors are inhibitors of their chemical processes that block or inhibit the initiation of intracellular changes. The change used herein is cell proliferation or differentiation or survival. Inhibitors of signal transduction pathways suitable for use in the present invention include, but are not limited to, receptor tyrosine kinase, non-receptor tyrosine kinase, SH2/SH3 domain blocker, serine/threonine kinase Inhibitors such as phospholipid inositol-3-OH kinase, inositol signal transduction, and Ras oncogene. Signal transduction pathway inhibitors can be used in combination with the compounds of the invention in the above compositions and methods.

Receptor kinase angiogenesis inhibitors have also been found to be useful in the present invention. Angiogenesis inhibitors with VEGFR and TIE-2 are described in the context of the above signal transduction inhibitors, both of which are receptor tyrosine kinases. Other inhibitors can be used in combination with the compounds of the invention. For example: an anti-VEGF antibody that does not recognize VEGFR (receptor tyrosine kinase) but binds to a ligand; a small molecule inhibitor of integrin (α _v β ₃ ) that inhibits angiogenesis; endostatin (Endostatin) and angiostatin (non-RTK) have also proven useful in combination with the compounds of the invention. An example of one of the VEGFR antibodies is bevacizumab (AVASTIN ^® ).

Several growth factor receptor inhibitors are still evolving and include ligand antagonists, antibodies, tyrosine kinase inhibitors, antisense oligonucleotides, and aptamers. Any such growth factor receptor inhibitor can be used in combination with the compounds of the invention for any of the compositions and methods/uses described herein. Trastuzumab (Herceptin ^® ) is an example of an anti-erbB2 antibody inhibitor of growth factor function. Anti-growth factor antibody inhibitor functions at one -erbB1 Examples cetuximab ^{(cetuximab) (Erbitux TM, C225} ). Bevacizumab (Avastin ^® ) is an example of a monoclonal antibody that targets VEGFR. Examples of small molecule inhibitors of the epidermal growth factor receptor include, but are not limited to, lapatinib (Tykerb ^® ) and erlotinib (TARCEVA ^® ). Imatinib mesylate (GLEEVEC ^® ) is one of the examples of PDGFR inhibitors. Examples of VEGFR inhibitors include pazopanib mAb ^{(pazopanib) (Votrient ®),} ZD6474, AZD2171, PTK787, sunitinib (sunitinib) and sorafenib (sorafenib).

An anti-microtubule or anti-mitotic agent is a phase-specific preparation that is active against microtubules of tumor cells during the M phase or mitosis phase of the cell cycle. Examples of anti-microtubule agents include, but are not limited to, diterpenes and vinca alkaloids.

Naturally derived diterpenes are phase specific anticancer agents for the G ₂ /M phase of the cell cycle. The diterpene is stabilized by binding to the β-tubulin subunit of the microtubule. Therefore, when mitosis is arrested, the disintegration of the protein also appears to be inhibited, and then the cells die. Examples of diterpenes include, but are not limited to, paclitaxel and its analog, docetaxel.

Pacific paclitaxel: 5β,20-epoxy-1,2α,4,7β,10β,13α-hexahydroxy yew-11-ene-9-one and (2 R ,3 S )- N -phenyl 4,10-diacetate 2-benzoate 13-ester formed from mercapto-3-phenylisoseuric acid; it is a natural diterpene product isolated from Taxus brevifolia The injection TAXOL ^® can be obtained from the product. It belongs to the taxane family of terpenes. First, in 1971, it was separated by Wani et al. (J. Am. Chem, Soc., 93: 2325 (1971)), who used chemical and X-ray crystallography to discriminate their structures. One of its activities is related to the ability of paclitaxel to bind to tubulin, thereby inhibiting the growth of cancer cells. Schiff et al., Proc. Natl, Acad, Sci. USA, 77: 1561-1565 (1980); Schiff et al., Nature, 277: 665-667 (1979); Kumar, J. Biol, Chem, 256: 10435- 10441 (1981). For the synthesis and anticancer activity of certain paclitaxel derivatives, see: DG Iingston et al., "Studies in Organic Chemistry", Volume 26, entitled "New Trends in Natural Product Chemistry in 1986 (New trends) In Natural Products Chemistry 1986)", Attur-Rahman, PW Le Quesne, Eds. (Elsevier, Amsterdam, 1986) pp 219-235.

Paclitaxel has been approved for clinical treatment of refractory ovarian cancer in the United States (Market et al., Yale Journal of Biology and Medicine, 64: 583, 1991; McGuire et al., Ann. Int. Med., 111: 273, 1989), and For the treatment of breast cancer (Jol. et al., J. Nat. Cancer Inst., 83: 1797, 1991). It is used to treat skin neoplasia (Einzig et. al., Proc. Am. Soc. Clin. Oncol., 20: 46) and head and neck cancer (Forastire et. al., Sem. Oncol., 20:56, 1990). Possible drug candidates. These compounds also have the potential to treat polycystic kidney disease (Woo et al, Nature, 368: 750. 1994), lung cancer and malaria. Patients receiving paclitaxel treatment inhibited bone marrow (multiple cell lines, Ignoff, RJ) during administration over a threshold concentration (50 nM) (Kearns, CM et al, Seminars in Oncology, 3 (6) p. 16-23, 1995) Et al, "Cancer Chemotherapy Pocket Guide", 1998).

European paclitaxel: (2 R , 3 S )- N -carboxy-3-phenylisosegic acid N - tert-butyl ester and 5β-20-epoxy-1,2α,4,7β,10β , 13α-hexahydroxy yew-11-ene-9-one 4-acetate 2-benzoate formed 13-ester, trihydrate; can be obtained from the commercial injection TAXOTERE ^® . European paclitaxel is indicated for the treatment of breast cancer. European docetaxel is a semi-synthetic derivative of paclitaxel (see above) which is a natural precursor (10-desylidene-baccatin III) extracted from the needles of European paclitaxel. )preparation. The limiting dose toxicity of paclitaxel in Europe is neutropenia.

The vinca alkaloids are phase-specific anti-tumor agents derived from the plant of the periwinkle plant. Vinca alkaloids act on the M phase (mitosis) of the cell cycle by specifically binding to tubulin. As a result, the bound tubulin molecules cannot be polymerized to form microtubules. The mitotic mitosis is stopped in the medium term, and then the cell is dead. Examples of vinca alkaloids include, but are not limited to, vinblastine, vinblastine, and vinorelbine.

Vinblastine: Vincaleukoblastine sulfate, VELBAN ^® injection available from the product. Although it may be a second-line therapy for a variety of different solid tumors, it is primarily suitable for the treatment of testicular cancer with a variety of different lymphomas, including Hodgkin's Disease; and lymphocytic and histiocytic lymphoma. The limiting dose side effect of vinblastine is myelosuppressive.

Vincentine (Vincristine): Vinblastine, 22-oxo-, sulfate, available from the product ONCOVIN ^® injection. Vinblastine is indicated for the treatment of acute leukemia and has also been found to be useful in the treatment of Hodgkin's disease and non-Hodgkin's lymphoma. The most common side effects of vinca alkaloids are hair loss and neurological effects, and milder myelosuppressive and gastrointestinal mucositis.

Vinorelbine: 3',4'-dihydro-4'-deoxy-C'-demethylvinblastine [R-(R*,R*)-2,3-dihydroxybutyrate Diacid salt (1:2)], which is a semi-synthetic vinca alkaloid obtained from the product of vinorelbine tartrate injection (NAVELBINE ^® ). Vinorelbine is indicated for use in a single preparation or in combination with other chemotherapeutic agents (eg, cisplatin) for the treatment of a variety of different solid tumors, specifically non-small cell lung cancer, advanced breast cancer, and hormone refractory prostate. cancer. The most common limiting dose side effect of vinorelbine is myelosuppressive.

Platinum coordination complexes are non-phase specific anticancer agents that interact with DNA. Palladium complexes enter the tumor cells under hydration and form inter- and inter-strand interchains with DNA. It has a negative biological effect on the tumor. Examples of palladium coordination complexes include, but are not limited to, cisplatin and carboplatin.

Cisplatin: cis-diamine dichloroplatinum, available from commercial PLATINOL ^® injection. Cisplatin is mainly used for the treatment of metastatic testicular pills with ovarian cancer and advanced bladder cancer. The main limiting dose side effects of cisplatin are nephrotoxicity (which may be controlled by drinking water and diuresis) and ototoxicity.

Carboplatin: Diamine [1,1-cyclobutane-dicarboxylate (2-)-O, O'] platinum, available from commercial PARAPLATIN ^® injection. Carboplatin is mainly used for the treatment of advanced ovarian cancer with the first line and the second line. The limiting dose toxicity of carboplatin is myelosuppressive.

The alkylating agent is not a phase specific anticancer agent, but is a strong electrophile. Usually, the alkylating agent is alkylated with the DNA through the nucleophilic moiety of the DNA molecule (eg, phosphate, amine, thiol, hydroxyl, carboxyl, and imidazolyl) to form a covalent link. Such alkylation can disrupt nucleic acid function and cause cell death. Examples of alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as: Busulfan; nitrosourea, such as: carmustine; and three Class, such as: dacarbazine.

Cyclophosphamide: 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphine 2-oxide monohydrate, which can be obtained from commercial injections or ingots. CYTOXAN ^® . Cyclophosphamide is indicated for use in the treatment of malignant lymphoma, multiple myeloma, and leukemia in a single formulation or in combination with other chemotherapeutic agents. The most common limiting dose side effects of cyclophosphamide are hair loss, nausea, vomiting, and leukopenia.

Melphalan: 4-[bis(2-chloroethyl)amino]-L-phenylalanine, ALKERAN ^® from which the injection or lozenge can be obtained from the product. Melphalan is indicated for the relief of multiple myeloma and unresectable ovarian epithelial cancer. The most common limiting dose side effect of melphalan is myelosuppression.

Chlorambucil (Chlorambucil): 4- [bis (2-chloroethyl) amino] benzenebutanoic acid, can be acquired from commercial LEUKERAN ^® lozenges. Chlorambucil is suitable for the treatment of chronic lymphocytic leukemia and malignant lymphoma, such as lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease. The most common limiting dose side effect of chlorambucil is myelosuppressive.

Busulfan: 1,4-butanediol dimethanesulfonate, available from MYLERAN ^® tablets. Busulfan is suitable for the treatment of chronic myelogenous leukemia. The most common limiting dose side effect of busulfan is myelosuppression.

Carmustine: 1,3-[bis(2-chloroethyl)-1-nitrourea, a single-bottle lyophilizate BiCNU ^® available from the product. Carmustine is suitable for use as a single agent or in combination with other agents for the treatment of brain tumors, multiple myeloma, Hodgkin's disease, non-Hodgkin's lymphoma. The most common limiting dose side effect of carmustine is delayed myelosuppression.

Dacarbazine: 5-(3,3-dimethyl-1-triazenyl)-imidazole-4-carboxamide, available in a single bottle of DTIC-Dome ^® . Dacarbazine is indicated for the treatment of metastatic malignant melanoma and can be used in combination with other agents used in second-line treatment of Hodgkin's disease. The most common limiting dose side effects of dacarbazine are nausea, vomiting and anorexia.

Antibiotic anticancer drugs are not phase specific agents that bind or interact with DNA. Often, these effects can result in a stable DNA complex or a break in the strand, disrupting the normal function of the nucleic acid and causing cell death. Examples of antibiotic anti-tumor agents include, but are not limited to, actinomycin (eg, dactinomycin), anthracyclines (eg, daunorubicin and doxorubicin); With bleomycin.

Dactinomycin, also known as actinomycin D, is available as an injectable COSMEGEN ^® from the product. Dactinomycin is indicated for the treatment of Wilm's tumor and rhabdomyosarcoma. The most common limiting dose side effects of actinomycin D are nausea, vomiting, and anorexia.

Daunorubicin: (8S-cis-)-8-ethenyl-10-[(3-amino-2,3,6-trideoxy-α-L-lyxose-peripheryl) Ethylhexyl)-oxo-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12naphthalenedione hydrochloride, available from commercially available lipids injectable DAUNOXOME ^® of the body or for injection of CERUBIDINE ^®. Daunorubicin is indicated for the induction of remission in the treatment of acute non-lymphocytic leukemia with advanced HIV-associated Kaposi's sarcoma. The most common limiting dose side effect of daunorubicin is myelosuppressive.

Cranberry (doxorubicin): (8S, 10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxose-piperanose)oxy]-8 -Hydroxyethyl hydrazino, 7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthalenedione hydrochloride, available from commercially available injectable RUBEX ^® or ADRIAMYCIN RDF ^® . Cranberry is mainly used for the treatment of acute lymphoblastic leukemia and acute myeloid leukemia, but it is also suitable for the treatment of certain solid tumors and lymphoma components. The most common limiting dose side effect of cranberries is myelosuppression.

Bleomycin is a mixture of cytotoxic glycopeptide antibiotics isolated from Streptomyces verticillus , which can be obtained from the product BLETHOXANE ^® . Bleomycin is indicated for use in a single formulation or in combination with other agents for the treatment of squamous cell carcinoma, lymphoma, and testicular cancer. The most common limiting dose side effects of bleomycin are lung and skin toxicity.

Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxin.

Epipodophyllotoxin is a phase-specific antitumor agent derived from Mandela. Epipodophyllotoxin usually affects the cell cycle S and G ₂ phases in cells, and forms a ternary complex with topoisomerase II and DNA, causing DNA strand breakage. After the strand breaks up, it causes cell death. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.

Etoposide: 4'-desmethyl-epipodophyllotoxin 9 [4,6-0-(R)-ethylidene-β-D-glucopyranoside, which can be obtained from commercial injections or The capsule's VePESID ^® , commonly referred to as VP-16. Etoposide is indicated for use as a single agent or in combination with other chemotherapeutic agents for the treatment of testicular and non-small cell lung cancer. The most common side effect of etoposide is myelosuppression. The tendency to develop leukopenia is more severe than thrombocytopenia.

Teniposide: 4'-desmethyl-epipodophyllotoxin 9 [4,6-0-(R)-thiophene methylene-β-D-glucopyranoside] can be obtained from commercial injections Liquid VUMON ^® , commonly referred to as VM-26. Teniposide is indicated as a single agent or in combination with other chemotherapeutic agents for the treatment of acute leukemia in children. The most common limiting dose side effect of teniposide is myelosuppressive. Teniposide can induce both leukopenia and thrombocytopenia.

An antimetabolite antineoplastic agent is a phase-in-phase anti-tumor agent that acts on the S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting the synthesis of purine or pyrimidine bases, thereby limiting DNA synthesis. Therefore, the S phase cannot be performed, and then the cells die. Examples of antimetabolite antineoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, thiophanate, thioguanine, and gemcitabine.

5-fluorouracil: 5-fluoro-2,4-(1H,3H)pyrimidinedione, which is commercially available as a fluorouracil. Administration of 5-fluorouracil inhibits thymidylate synthesis and also enters RNA and DNA. A typical result is cell death. 5-fluorouracil is indicated for use as a single agent or in combination with other chemotherapeutic agents for the treatment of breast, colon, rectal, gastric and pancreatic cancers. The limiting dose side effects of 5-fluorouracil are myelosuppressive and mucosal. Other fluoropyrimidine analogs include 5-fluorodeoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.

Cytarabine: 4-amino-1-β-D-furan arabinosyl-2(1 H )-pyrimidinone, available from commercial CYTOSAR-U ^® , commonly known as Ara-C. The cytarabine has a cell phase specificity in the S-phase, and cytarabine enters the end of the extended DNA strand and inhibits DNA strand elongation. Cytarabine is indicated for use in the treatment of acute leukemia in a single agent or in combination with other chemotherapeutic agents. Other cytidine analogs include 5-azacytidine and 2',2'-difluorodeoxycytidine (gemcitabihe). Cytarabine induces leukopenia, thrombocytopenia, and mucositis.

Hydrogenthiopurine: 1,7-dihydro-6H-indole-6-thione monohydrate, available from commercial PURINETHOL ^® . Hydrogenthioguanidine has cell phase specificity in the S-phase and inhibits DNA synthesis, but its mechanism is still unclear. Hydrothyl sulfonium is suitable for treating acute leukemia in a single agent or in combination with other chemotherapeutic agents. Hydrogenthioguanidine may have myelosuppressive and gastrointestinal mucositis side effects at high doses. A suitable thiosulfonium oxime analog is azathioprine.

Thioguanine: 2-amino-1,7-dihydro-6H-indole-6-thione, available from the product TABLOID ^® . Thioguanine has a phase-specificity in the S-phase and inhibits DNA synthesis, but its mechanism is still unclear. Thioguanine is indicated for use as a single agent or in combination with other chemotherapeutic agents for the treatment of acute leukemia. The most common limiting dose side effects of administration to thioguanine are myelosuppression, including leukopenia, thrombocytopenia, and anemia. However, gastrointestinal side effects can occur and the dose may be limited. Other purine analogs include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine.

Gemcitabine: 2'-deoxy-2', 2'-difluorocytidine monohydrochloride (β-isomer), available from commercial GEMZAR _® . Gemcitabine has cell phase specificity for the S-phase and blocks cell progression through the G1/S boundary. Gemcitabine is indicated for use in combination with cisplatin for the treatment of locally advanced non-small cell lung cancer and can be used alone for the treatment of locally advanced pancreatic cancer. The most common limiting dose side effects of gemcitabine are myelosuppressive, including leukopenia, thrombocytopenia, and anemia.

Methotrexate: N -[4[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzimidyl]-L-glutamic acid, Obtained methotrexate sodium from the product. Methotrexate has cell phase specificity for the S-phase and inhibits DNA synthesis, repair and/or replication by inhibiting dehydrofolate reductase required for the synthesis of purine nucleotides and thymidylate. Methotrexate is indicated as a single agent or in combination with other chemotherapeutic agents for the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, and carcinoma of the breast, head, neck, ovary and bladder . Possible side effects of administration of methotrexate are myelosuppressive (leukopenia, thrombocytopenia, and anemia) and mucositis.

Camptothecin (including camptothecin and camptothecin derivatives) can achieve or is developing topoisomerase I inhibitors. The cytotoxic activity of camptothecin is related to its topoisomerase I inhibitory activity. Examples of camptothecins include, but are not limited to, irinotecan, topotecan, and various optical types 7-(4-methylphenidate) described below. Methyl-methylene)-10,11-extended ethyldioxy-20-camptothecin.

Irinotecan HCl: (4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidinyl)carbonyloxy]-1H-pyrano[3', 4',6,7]吲哚 And [1,2-b]quinoline-3,14(4H,12H)-dione hydrochloride can be obtained from the commercial CAMPTOSAR ^® .

Irinotecan is a derivative of camptothecin that binds to the topoisomerase I-DNA complex along with its active metabolite SN-38. Xianxin, which is cytotoxic by irreversible double-strand breaks caused by the interaction of topoisomerase I:DNA: irinotecan or SN-38 ternary complex with replication enzymes. Irinotecan is indicated for the treatment of metastatic cancer of the colon or rectum. The limiting dose side effects of irinotecan HCl are myelosuppressive (including neutropenia) and GI effects (including diarrhea).

Topotecan HCl: (S)-10-[(Dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4', 6,7]吲哚 And [1,2-b]quinoline-3,14-(4H,12H)-dione monohydrochloride, the injection HYCAMTIN ^® can be obtained from the product. Topotecan is a camptothecin derivative that binds to the topoisomerase I-DNA complex to prevent the topoisomerase I from being re-bonded by the rupture of the DNA molecule. Topotecan is indicated for second-line treatment of metastatic carcinoma of the ovary and small cell lung cancer. The limiting dose side effect of topotecan HCl is myelosuppressive, mainly neutropenia.

Compound method General synthetic reaction diagram

The compounds of the invention can be made by a variety of different methods, including conventional standard methods of synthesis. The general synthetic procedures are exemplified below, and then the compounds of the invention are prepared in the working examples. It is well understood by those skilled in the art that if the substituents described herein are not compatible with the synthetic methods described herein, the substituents may be protected with suitable protecting groups which are stable to the reaction conditions. The protecting group can be removed at an appropriate stage during the reaction to provide the desired intermediate or target compound. In all of the reaction schemes described below, depending on the general principles of synthetic chemistry, it is desirable to use protecting groups for sensitive or reactive groups. The protecting group is operated according to the standard method of organic synthesis method (Protecting Groups in Organic Synthesis , TW Green and PGM Wuts (1991 ) , John Wiley &Sons", wherein the disclosure of the protective group has been cited The manner is incorporated herein). Such groups will be removed at a convenient stage in the synthesis of the compound by methods well known to those skilled in the art. The process and reaction conditions and the order of execution thereof should be selected in accordance with the process of the compounds of the present invention.

Those skilled in the art will be able to synthesize a compound of formula (I) with a pharmaceutically acceptable derivative and a salt thereof in accordance with the following reaction schemes 1 to 5. In the following description, the group is as defined above for the compound of formula (I) unless otherwise stated. The starting material can be obtained from a commercial product or from a starting material obtained from a commercial product by a method known to those skilled in the art.

The compound of formula (I) can be prepared according to the method shown in Figure 1. The appropriately substituted acid with an amine A are formed under the reaction conditions Amides bond, such as: using HOBt in DMF, the EDC, and Et ₃ N, to produce an intermediate aryl bromide B. Intermediate B can be coupled to the dihydroxyborate intermediate C under palladium coupling conditions, such as the use of PdCl ₂ (dppf) and Cs ₂ CO ₃ to produce intermediate D. Removal of the p-methoxybenzyl (PMB) or benzyl (Bn) moiety from the H ₂ atmosphere in the presence of palladium on carbon produces the compound of formula (I).

Intermediate D can also be prepared as shown in Figure 2. The aryl bromide B can be converted to a dihydroxyborate under suitable conditions, such as: 1,4-di PdCl ₂ (dppf) and KOAc were used in the alkane to produce the dihydroxyborate intermediate E. The intermediate D is then produced by coupling of the appropriately substituted 3-bromopyridine under palladium coupling conditions (e.g., using PdCl ₂ (dppf) and Cs ₂ CO ₃ ) with intermediate E. The intermediate D can be further converted to form a compound of formula (I), similarly to the conditions of reaction of Figure 1.

Intermediate D can also be prepared as shown in Figure 3. The aryl bromide F can be converted to a dihydroxyborate under suitable conditions, such as: 1,4-two PdCl ₂ (dppf) and KOAc were used in the alkane to produce the dihydroxyborate intermediate G. The methyl ester intermediate G can be converted to the primary guanamine intermediate H using ammonia under basic conditions. The appropriately substituted 3-bromopyridine is then coupled with the intermediate H under palladium coupling conditions (eg, using PdCl ₂ (dppf) with Cs ₂ CO ₃ ) to give intermediate I. The intermediate I can be further coupled with an appropriately substituted aryl bromide under suitable conditions, such as: 1,4-two Pd ₂ (dba) ₃ , Xantphos and Cs ₂ CO ₃ are used in the alkane to convert to intermediate D. The intermediate D can be further converted to form a compound of formula (I) similarly to the conditions of Figure 1.

Intermediate I can also be prepared as shown in Figure 4. The aryl bromide intermediate J can be coupled to the substituted pyridine dihydroxyborate under palladium coupling conditions (e.g., using PdCl ₂ (dppf) and Cs ₂ CO ₃ ) to produce intermediate I. Intermediate I can be further converted to a compound of formula (I) as shown in Schemes 3 and 1.

The compound of formula (I) can also be prepared as shown in Figure 5. The appropriately substituted acid A can be coupled to an appropriately substituted pyridin-3-yl dihydroxyborate under palladium coupling conditions (e.g., using PdCl ₂ (dppf) and Cs ₂ CO ₃ ) to produce intermediate K. The protection of the p-methoxybenzyl (PMB) or benzyl (Bn) moiety is removed from the H ₂ atmosphere by the intermediate K in the presence of palladium on carbon to give the intermediate L. Of the appropriately substituted acid intermediate by an amine and then L, is formed under conditions of Amides key (eg: using HOBt, EDC, and Et ₃ N in DMF) coupling a compound of formula (I).

experiment

The following examples illustrate the invention. The examples are not intended to limit the scope of the invention, and are intended to be illustrative of the preparation and use of the compounds, compositions, and methods of the invention. While the invention has been described with respect to the specific embodiments of the present invention, various modifications and changes may be made without departing from the spirit and scope of the invention. Unless otherwise indicated, reagents may be obtained commercially or prepared according to procedures in the literature. The codes and practices used in the description of these processes, reaction diagrams, and examples are consistent with, for example, the Journal of the American Chemical Society or the Journal of Biological. Chemistry) and other modern scientific literature.

In the example:

Chemical shifts are expressed in parts per million (ppm). The coupling constant (J) is expressed in Hertz (Hz) units. The peak type indicates apparent multimodality, and is s (single peak), d (double peak), t (parallel peak), q (peak), dd (double double peak), dt (double peak) ), dq (double peak), m (multimodal), br (wide peak).

Fast column chromatography is performed on silica gel.

The naming program used is ACDLABs 11.0 Namebatch, ACD IUPAC, or ChemDraw ^® .

abbreviation

Intermediate method

Intermediate 1: 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Heterocyclic pentan-2-yl)pyridine

Step 1: 3-bromo-5-ethoxypyridine

A mixture of 5-bromo-3-ol _{(70g, 402mmol), K 2} CO 3 (111g, 805mmol) and iodoethane (69.0g, 443mmol) of DMF (700mL) was stirred at 25 ℃ 16h. The mixture was then concentrated to give the residue, extracted with DCM (2 x 200mL), dried over sodium sulfate, filtered, and concentrated to yield 3-bromo-5-ethoxy-pyridine (53g, 218mmol, 54.2% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.19-8.17 (m, 2H), 7.60-7.59 (m, 1H), 4.13-4.07 (m, 2H), 1.40 (t, J = 7.0 Hz, 3H); - LCMS m/z 202 (M+H).

Step 2: 3-Bromo-5-ethoxypyridine 1-oxide

m- CPBA (67.9 g, 393 mmol) was slowly added over 30 minutes over a solution of 3-bromo-5-ethoxypyridine (53 g, 262 mmol) in EtOAc. After the resulting solution was stirred for 15H, the mixture was washed with NaS ₂ O ₃ solution, extracted with DCM (2 x 300mL), dried over sodium sulfate, filtered, the organic phase was concentrated to yield 3-bromo-5-ethoxy-pyridine 1-oxide product (40g, 165mmol, 62.9% ^{yield): 1 H NMR (400MHz,} CD 3 OD) δ 8.19-8.18 (m, 1H), 8.08-8.07 (m, 1H), 7.50-7.49 (m, 1H), 4.17-4.15 (d, J = 8.8 Hz, 2H), 1.43 (t, J = 7.0 Hz, 3H); ES-LCMS m/z 217 (M+H).

Step 3: 5-Bromo-2-chloro-3-ethoxypyridine

0 ℃ containing the 3-bromo-5-ethoxy-pyridine-1-oxide (40g, 183mmol) of DCM (200mL) solution was added slowly over 30 minutes to POCl ₃ (159mL, 1701mmol). The resulting solution was then allowed to warm to 45 ° C over 15 hours. The mixture was concentrated, extracted with DCM (2 x 200mL), dried over sodium sulfate, filtered, and concentrated to yield 5-bromo-2-chloro-3-ethoxy-pyridine (30g, 60.9mmol, 33.2% yield): ¹ H NMR (400MHz, CD ₃ OD) δ 8.00-7.99 (d, J = 2.0 Hz, 1H), 7.65-7.64 (d, J = 2.0 Hz, 1H), 4.17 - 4.12 (m, 2H), 1.44 (t , J = 7.0 Hz, 2H); ES-LCMS m/z 235 (M+H).

Step 4: 5-Bromo-3-ethoxy-2-((4-methoxybenzyl)oxy)pyridine

To a mixture of (4-methoxyphenyl)methanol (16.71 g, 121 mmol) in DMF (200 mL) After stirring the mixture for 30 min, 5-bromo-2-chloro-3-ethoxypyridine (26 g, 110 mmol) was added to the above mixture; the mixture was stirred at 80-90 ° C for 12 h. Add H ₂ O (20mL) suspension of the reaction mixture, extracted with DCM (2 x 200mL), dried over sodium sulfate, filtered, and concentrated to yield residue was purified by column chromatography (10% EA / 90% PE , 360g meteorite column). All the fractions containing the product (EA/PE = 5:1, R _f = 0.5) were judged by TLC to be combined and concentrated to give 5-bromo-3-ethoxy-2-((4-methoxy) as a white solid. Benzomethyl)oxy)pyridine (36 g, 74.5 mmol, 67.8% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.71 (d, J = 2.0 Hz, 1H), 7.36-7.31 (m, 3H) ), 6.89-6.87 (m, 2H), 5.27 (s, 2H), 4.05-4.00 (m, 2H) 3.77 (s, 3H), 2.37 (d, J = 7.0 Hz, 3H); ES-LCMS m/ z 338 (M+H).

Step 5: 3-Ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Cyclopentan-2-yl)pyridine

Containing 5-bromo-3-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (10 g, 29.6 mmol), 4, 4, 4' in a nitrogen atmosphere at 20 ° C , 4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) (8.26 g, 32.5 mmol) with KOAc (7.25 g, 73.9mmol) of 1,4-two A full amount of PdCl ₂ (dppf) (1.082 g, 1.478 mmol) was added in one portion of the alkane (250 mL) solution. The reaction mixture was stirred at 100 ° C for 3 h. The mixture was filtered and the filtrate was concentrated in vacuo to give crude material. The crude product was purified by column chromatography (PE/EA = 10:1). All the fractions containing the product (PE/EA = 10:1, R _f = 0.6) were judged by TLC to be combined and concentrated to give 3-ethoxy-2-((4-methoxybenzyl) as a white solid. Oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (9.2 g, 23.88 mmol, 81.0% yield) : ¹ H NMR (400MHz, CDCl ₃ ) δ 8.10 (s, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.33 (s, 1H), 6.88-6.85 (m, 2H), 5.45 (s, 2H), 4.11-4.06 (m, 2H), 3.78 (s, 3H), 1.43 (t, J = 7.0 Hz, 3H), 1.33 (s, 12H); ES-LCMS m/z 386.0 (M+H) .

Intermediate 2: 4-(2-(Benzyloxy)ethoxy)-3-(trifluoromethyl)aniline

Step 1: 1-(2-(Benzyloxy)ethoxy)-4-nitro-2-(trifluoromethyl)benzene

K ₂ CO ₃ (6.61 g, 47.8 mmol) was added to a mixture of 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (5 g, 23.91 mmol) in DMF (50 mL) 2-(Benzyloxy)ethanol (4.00 g, 26.3 mmol). The mixture was stirred at 110 C for 12 h. LCMS and TLC (PE/EA = 5:1, _Rf = 0.4) showed that the reaction was completed. The mixture is filtered and the filtrate is concentrated to give a crude material which is purified on EtOAc EtOAc EtOAc (td. 7.1g, 18.18mmol, 76.0% yield): ¹ H NMR (400MHz, CDCl ₃ ) 8.49 (d, J = 2.4 Hz, 1H), 8.38 (d, J = 9.2 Hz, 1H), 7.54 - 7.28 (m) , 5H), 7.13 (d, J = 8, 4 Hz, 1H), 4.56 (s, 2H), 4.36 (t, J = 4.8 Hz, 2H), 3.89 (t, J = 3.6 Hz, 2H); LCMS m/z 342 (M + H).

Step 2: 4-(2-(Benzyloxy)ethoxy)-3-(trifluoromethyl)aniline

Add zinc (15.52) to a mixture of 1-(2-(benzyloxy)ethoxy)-4-nitro-2-(trifluoromethyl)benzene (8.1 g, 23.73 mmol) in MeOH (100 mL) g, 237mmol) and _{NH 4 Cl (12.70g, 237mmol)} . The mixture was stirred at 20 ° C for 3 h. LCMS showed the reaction was completed. The mixture was filtered, and the filtrate was concentrated to give a crude material which was purified on a silica gel column (PE/EA = 5:1, _Rf = 0.4) to give 4-(2-(phenylmethyloxy)ethoxy)-3 -(Trifluoromethyl)aniline (5.1 g, 14.40 mmol, 60.7% yield). _{^{1 H NMR (400MHz, CDCl 3}} ) 7.35-7.24 (m, 5H), 6.81 (t, J = 8.4Hz, 2H), 6.78 (d, J = 2.8Hz, 1H), 4.63 (s, 2H), 4.13 (t, J = 4.8 Hz, 2H), 3.83 (t, J = 3.6 Hz, 2H); ES-LCMS m/z 312 (M+H).

Intermediate 3: 4-(3-((Tertiary butyldimethylmethyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)aniline

Step 1: 2,2-Dimethyl-3-(2-(trifluoromethyl)phenyl)propanoic acid ethyl ester

n- BuLi (24.60 mL, 61.5 mmol) was added dropwise to a mixture of diisopropylamine ( 8.00 mL, 57.1 mmol) in THF (300 mL). The mixture was stirred at 0 ° C for 1 h. A solution of ethyl isobutyrate (6.12 g, 52.7 mmol) in THF (2 mL) was then added to a mixture cooled to -30. The mixture was stirred at -30 ° C for 1 h. A solution of 1-(bromomethyl)-2-(trifluoromethyl)benzene (10.5 g, 43.9 mmol) in THF (5 mL). All the mixture was stirred at -30 ° C for 3 h and then stirred at 25 ° C for 12 h. NH ₄ Cl aqueous suspension using a mixture of the reaction, extracted with EA. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by column chromatography (PE/EA = 200:1). All the fractions containing the product (PE/EA = 10:1, R _f = 0.6) were judged by TLC to be combined and concentrated to give a pale yellow solid of 2,2-dimethyl-3-(2-(trifluoro) Ethyl phenyl) propionic acid ethyl ester (10 g, 35.3 mmol, 80.0% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.62 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.14 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H), 1.18 (s, 6H); ES-LCMS m/z 275 (M+H).

Step 2: Ethyl 2,2-dimethyl-3-(4-nitro-2-(trifluoromethyl)phenyl)propanoate

After cooling to 0 ℃ containing the 2,2-dimethyl-3- (2- (trifluoromethyl) phenyl) propanoic acid ethyl ester (10g, 36.5mmol) of _{H 2 SO 4 (5mL, 94mmol} ) Potassium nitroperoxylate (4.05 g, 40.1 mmol) was added portionwise over the solution. The mixture was stirred at 0 ° C for 30 min. The mixture was poured into ice-water and extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to yield of 2,2-dimethyl-3-(4-nitro-2-(trifluoromethyl)phenyl)propanoic acid Base ester (8.5 g, 24.54 mmol, 67.3% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.59 (d, J = 2.4 Hz, 1H), 8.47 (dd, J = 2.4, 8.8 Hz, 1H ), 7.82 (d, J = 8.4 Hz, 1H), 5.97-5.83 (m, 2H); ES-LCMS m/z 320 (M+H).

Step 3: 3-(4-Amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoic acid ethyl ester

Ethyl 2,2-dimethyl-3-(4-nitro-2-(trifluoromethyl)phenyl)propanoate (8.5 g, 26.6 mmol) and Pd/C (0.283 g, 2.66) The mmol(M) (50 mL) reaction mixture was hydrogenated using an H-tube (conditions: 50 ° C, 50 psi, 24h). The mixture was filtered and the filtrate was concentrated. The crude product was purified by column chromatography (PE/EA = 10:1). All fractions containing the product (PE/EA = 5:1, _Rf = 0.4) were judged by TLC to be combined and concentrated to give 3-(4-amino-2-(trifluoromethyl)phenyl. -2,2-Dimethylpropionic acid ethyl ester (7 g, 22.42 mmol, 84.0% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ: 6.98 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 6.71 (dd, J = 2.4, 8.4 Hz, 1H), 4.15 (q, J = 6.8 Hz, 2H), 3.00 (s, 2H), 1.25 (t, J = 7.2 Hz, 3H), 1.14 (s, 6H); ES-LCMS m/z 290 (M+H).

Step 4: 3-(4-Amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropan-1-ol

Add in portions in a mixture of THF (200 mL) containing ethyl 3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (2 g, 6.91 mmol) LAH (0.525 g, 13.83 mmol). The mixture was stirred at 25 ° C for 10 h. The mixture was quenched with 15% aqueous NaOH (10 mL). The mixture was dehydrated over sodium sulfate. The mixture was filtered and the filtrate was concentrated. The residue was purified by vermiculite column chromatography (PE/EA = 8:1). All the fractions containing the product (PE/EA = 2:1, _Rf = 0.35) were determined by TLC to be combined and concentrated to give 3-(4-amino-2-(trifluoromethyl) as a pale yellow oil. Phenyl)-2,2-dimethylpropan-1-ol (1.1 g, 4.45 mmol, 64.4% yield): ¹ H NMR (400 MHz,MeOD) δ: 7.17 (d, J = 8.4 Hz, 1H) ), 6.98 (d, J = 2.4 Hz, 1H), 6.84 (dd, J = 2.4, 8.0 Hz, 1H), 3.31 (s, 2H), 2.67 (d, J = 1.2 Hz, 2H), 0.84 (s) , 6H); ES-LCMS m/z 248 (M+H).

Step 5: 4-(3-((Tertiary butyl dimethyl decyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)aniline

Addition of imidazole to a mixture of 3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropan-1-ol (300 mg, 1.213 mmol) in DCM (150 mL) 124 mg, 1.820 mmol) and TBSCl (219 mg, 1.456 mmol). The mixture was then stirred at 25 ° C for 5 h. The mixture was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC (PE / EA = 2: 1, R f = 0.5) yielded the pale yellow solid of 4- (3 - ((tert-butyl-dimethyl-Si-alkyl) oxy) -2,2 - dimethylpropyl)-3-(trifluoromethyl)aniline (350 mg, 0.930 mmol, 77.0% yield): ¹ H NMR (400 MHz, CD ₃ Cl) δ: 7.14 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 2.8 Hz, 1H), 6.70 (dd, J = 2.8, 8.4 Hz, 1H), 3.20 (s, 2H), 2.62 (d, J = 1.2 Hz, 2H), 0.87 ( s, 9H), 0.73 (s, 6H), 0.00 (s, 6H); ES-LCMS m/z 362 (M+H).

Intermediate 4: 2-(4-bromo-2-fluorophenyl)acetic acid

Step 1: 2-(4-Bromo-2-fluorophenyl)acetonitrile

A suspension of NaCN (2.085 g, 42.5 mmol) in DMF (20 mL) was added to a solution containing 4-bromo-1-(bromomethyl)-2-fluorobenzene (5.7 g, 21.27 mmol) in DMF (20 mL) . The mixture was stirred at 26 ° C for 10 h. The solution was then concentrated, and dissolved points between EA and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting 2-(4-bromo-2-fluorophenyl)acetonitrile (4.01 g, 18.74 mmol, 88.0% yield) was used for the next step without further purification. TLC (PE/EA = 1/1, _Rf 0.5): ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.24-7.37 (m, 3H), 3.70 (s, 2H).

Step 2: 2-(4-Bromo-2-fluorophenyl)acetic acid

A solution of 2-(4-bromo-2-fluorophenyl)acetonitrile (4.01 g, 18.74 mmol) in MeOH (30 mL) The mixture was stirred at 100 ° C for 12 h. The mixture was cooled to room temperature. The solution was then concentrated, and dissolved points between EA and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting 2-(4-bromo-2-fluorophenyl)acetic acid (4.13 g, 17.72 mmol, 95.0% yield) was used for the next step without further purification.

TLC (PE/EA = 1/1, _Rf = 0.4): ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.22-7.31 (m, 2H), 7.13 (t, J = 8.05 Hz, 1H), 3.67 (s , 2H); ES-LCMS m/z 232.9 (M+H).

Intermediate 5: 2-(Benzyloxy)-4-ethoxy-5-iodopyridine

Step 1: 4-Ethoxypyridine 1-oxide

Sodium ethoxide (48.6 g, 714 mmol) was added to a mixture of 4-nitropyridine 1-oxide (50 g, 357 mmol) in THF (500 mL). The mixture was stirred at 25 ° C for 16 h. The reaction residue is concentrated. The crude product was purified by flash column chromatography (DCM /MeOH = 25:1). All the fractions containing the product (DCM / MeOH = 25:1, R _f = 0.6) were judged by TLC to be combined and concentrated to give 4-ethoxypyridine 1-oxide (25 g, 162 mmol, 45.3%) Yield: ¹ H NMR (400 MHz, CD ₃ OD) δ 8.20-8.18 (m, 2H), 7.11-7.10 (m, 2H), 4.21-4.15 (m, 2H), 1.42 (t, J = 7.2 Hz) , 3H); ES-LCMS m/z 140.0 (M+H).

Step 2: 4-Ethoxypyridin-2-ol

A mixture of acetic anhydride (36.7 g, 359 mmol) containing 4-ethoxypyridine 1-oxide (5 g, 35.9 mmol) was taken. The solvent was then removed in vacuo, and the residue was dissolved in MeOH (25mL) and H ₂ O (25mL), stirred for 16h at 25 ℃. The mixture was concentrated. The crude product was purified by flash column chromatography (DCM /MeOH = 10:1). All the fractions containing the product (DCM / MeOH = 10:1, _Rf = 0.6), which were judged by TLC, were combined and concentrated to give 4-ethoxypyridin-2-ol (2.5 g, 16.17 mmol, 45.0% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.28 (d, J = 7.6 Hz, 1H), 6.07 (d, J = 3.2, 7.2 Hz, 1H), 5.86-7.85 (d, J = 2.4 Hz, 1H), 4.06-4.01 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H); ES-LCMS m/z 140.0 (M+H).

Step 3: 4-Ethoxy-5-iodopyridin-2-ol

To a mixture of 4-ethoxypyridin-2-ol (2.5 g, 17.97 mmol) in EtOAc (30 mL) The mixture was stirred at 80 ° C for 16 h. The mixture was concentrated and purified by preparative HPLC (MeCN / H ₂ O as the eluent, acidic conditions) to give 4-ethoxy-5-iodo-2-ol as a yellow solids (1.2g, 4.30mmol, 23.9% yield Rate): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.70 (s, 1H), 5.92 (s, 1H), 4.15 - 4.10 (m, 2H), 1.48 (t, J = 6.8 Hz, 3H); - LCMS m/z 265.8 (M+H).

Step 4: 2-(Benzyloxy)-4-ethoxy-5-iodopyridine

Add (bromomethyl)benzene (619 mg, 3.62 mmol) and silver carbonate (1665 mg, 6.04 mmol) to a mixture of 4-ethoxy-5-iodopyridin-2-ol (800 mg, 3.02 mmol) in THF (10 mL) ). The mixture was stirred at 70 ° C for 16 h. The reaction residue was filtered and the filtrate was concentrated. The mixture was diluted with water and extracted with DCM. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting 2-(benzyloxy)-4-ethoxy-5-iodopyridine (800 mg, 1.915 mmol, 63.4% yield) was used in the next step without further purification: ¹ H NMR (400 MHz, CDCl3) δ 8.28(s,1H), 7.45-7.43(m,2H), 7.38-7.36(m,3H),6.22(s,1H),5.33(s,2H),4.12-4.07(m,2H), 1.48 (t, J = 6.8 Hz, 3H); ES-LCMS m/z 355.9 (M+H).

Intermediate 6: 5-(1,1,1-trifluoro-2-methylpropan-2-yl) Zyrazin-3-amine

Step 1: 5,5,5-Trifluoro-4,4-dimethyl-3-oxo-valeronitrile

N- BuLi (56.4 mL, 141 mmol) was added to a mixture of EtOAc (300 mL). The mixture was stirred at -30 ° C for 30 min. Then, 3,3,3-trifluoro-2,2-dimethylpropionic acid methyl ester (15 g, 88 mmol) was added dropwise to the mixture. The mixture was stirred at 25 ° C for 10 h. NH ₄ Cl aqueous suspension using a mixture of the reaction, DCM / MeOH: extraction (101). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (PE/EA = 10:1). All fractions containing the product (PE/EA = 5:1, _Rf = 0.6) were judged by TLC to be combined and concentrated to give 5,5,5-trifluoro-4,4-dimethyl- 3-oxo-pentanenitrile (5g, 27.9mmol, 31.7% ^{yield): 1 H NMR (400MHz,} CDCl 3) δ: 3.75 (s, 2H), 1.41 (s, 6H).

Step 2: 5-(1,1,1-Trifluoro-2-methylpropan-2-yl) Zyrazin-3-amine

Was added NaHCO ₃ (3.94g, 46.9mmol) was cooled to 0 ℃ in the hydroxyl group-containing amine hydrochloride (3.10g, 44.7mmol) of H (25mL) ₂ O in the mixture was adjusted to pH = 7.5. A solution of 5,5,5-trifluoro-4,4-dimethyl-3-oxovaleronitrile (4 g, 22.33 mmol) in MeOH (25 mL) was then added. The mixture was stirred at 65 ° C for 15 h. After cooling, the mixture was acidified to pH = 1.0 using concentrated HCl and refluxed for 2 h. After cooling, the mixture was neutralized with 4 M NaOH to pH = 8.0. The mixture was extracted with DCM / MeOH (10:1). The organic layer was dried over sodium sulfate, filtered and concentrated to give 5-(1,1,1-trifluoro-2-methylpropan-2-yl) Zylin-3-amine (2 g, 9.06 mmol, 40.6% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.78 (s, 1H), 3.93 (s., 2H), 1.51 (s, 6H); - LCMS m/z 195 (M + 1).

Intermediate 7: 3-(4-methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)aniline

Step 1: 4-Methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1 H -imidazole

A suspension of 4-methyl-1 H -imidazole (1.178 g, 14.35 mmol) in DMF (15 mL) was added to 1-fluoro-3-nitro-5-(trifluoromethyl)benzene (2 g, 9.56) Methyl) in DMF (15 mL). Cs ₂ CO ₃ (6.23 g, 19.13 mmol) was added, and the mixture was stirred at 80 ° C for 8 h. After the mixture was cooled to room temperature, the solution was concentrated, and between EA and saturated NaHCO ₃ solution was divided dissolved. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by column chromatography (PE/EA = 5:1). All the fractions containing the product (PE/EA = 1:1, R _f = 0.5) were judged by TLC to be combined and concentrated to give 4-methyl-1-(3-nitro-5-(3) as a pale yellow solid. Fluoromethyl)phenyl)-1 H -imidazole (800 mg, 2.95 mmol, 30.8% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.61-8.78 (m, 1H), 8.44 - 8.51 (m, 1H), 8.31-8.39 (m, 2H), 7.55 (s, 1H), 2.27 (s, 3H); ES-LCMS m/z 272.0 (M+H).

Step 2: 3-(4-Methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)aniline

Add a suspension of 4-methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1 H -imidazole (800 mg, 2.95 mmol) in MeOH (15 mL) to Pd/c (8.26 mg, 0.078 mmol) in MeOH (15 mL). The mixture was stirred at 25 ° C under hydrogen atmosphere for 5 h. The solution was then concentrated, and dissolved points between EA and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/H ₂ O as eluting solvent, basic conditions) to yield 3-(4-methyl- 1H -imidazol-1-yl)-5-(trifluoromethyl) as a white solid. Aniline (321.83 mg, 1.334 mmol, 86.0% yield). TLC (PE/EA = 1:1, _Rf = 0.3): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.98 (s, 1H), 7.24 (s, 1H), 7.02-6.76 (m, 3H), 2.31-2.17 (m, 3H); ES-LCMS m/z 242.1 (M+H).

Intermediate 8: 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetonitrile

Step 1: 5-Nitro-3-(trifluoromethyl)pyridin-2-ol

Of ice containing 3- (trifluoromethyl) pyridin-2-ol (4g, 24.53mmol) of _{H 2 SO 4 (26.1mL, 491mmol} ) was added dropwise a solution of nitric acid (1.206mL, 27.0mmol). After 30 minutes, the ice bath was left and the reaction was stirred at 26 ° C for 10 h. The reaction mixture was added to 120 g of ice. The resulting precipitate was collected by filtration, rinsed using H ₂ O and air-dried to produce a first crop. After the mother liquor was evaporated to less than 100 mL, another batch of product was obtained, which was cooled on an ice bath and adjusted to pH = 8 with NaOH. The mixture was extracted with EA (100 mL). The organic layer was dried and concentrated to give crystals crystals crystals crystals crystals crystals ¹ H NMR (400 MHz, CD ₃ OD) δ: 8.86 (d, J = 3.1 Hz, 1H), 8.85 (d, J = 2.6 Hz, 1H); ES-LCMS m/z 209.0 (M+H).

Step 2: 2-Chloro-5-nitro-3-(trifluoromethyl)pyridine

SOCl ₂ (18.45 mL, 253 mmol) was added to a solution of 5-nitro-3-(trifluoromethyl)pyridin-2-ol (2.63 g, 12.64 mmol). DMF (1.957 mL, 25.3 mmol) was added and the mixture was taken at 100 ° C for 10 h. The solution was then concentrated, and dissolved points between EA and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (2.46 g, 10.86 mmol, 86% yield) was used in the next step without further purification. TLC (PE/EA = 5:1, _Rf = 0.6): ¹ H NMR (400 MHz, CDCl ₃ ) δ: 9.23 - 9.59 (m, 1H), 8.79 (d, J = 2.4 Hz, 1H).

Step 3: 2-Cyano-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetic acid tert-butyl ester

(15mL) was added _{K Z CO 3 (854mg, 6.18mmol} ) in THF containing 2-cyanoacetic acid tert-butyl ester (523mg, 3.71mmol) of. Then 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (700 mg, 3.09 mmol) was added to the mixture and the mixture was taken at 50 ° C for 10 h. The solution was then concentrated, and dissolved points between EA and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (DCM / MeOH = 20: 1 , R f = 0.4), generating a light yellow solid of 2-cyano-2- (5-nitro-3- (trifluoromethyl) pyridin - 2-Benzyl acetate, tert-butyl acetate (1 g, 3.02 mmol, 98.0% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.99 (d, J = 2.43 Hz, 1H), 8.36 (d, J = 2.43 Hz, 1H), 3.35 (s, 1H), 1.49 (d, J = 1.54 Hz, 9H); ES-LCMS m/z 276 (M-55).

Step 4: 2-(5-Nitro-3-(trifluoromethyl)pyridin-2-yl)acetonitrile

Add in a solution of 2- cyano-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetic acid tert-butyl ester (1.06 g, 3.20 mmol) in MeOH (80 mL) HCl (20 mL, 3.20 mmol). The mixture was taken at 70 ° C for 10 h. The solution was then concentrated, and dissolved points between EA and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetonitrile (402 mg, 1.739 mmol, 54.4% yield) was used for the next step without further purification. TLC (PE/EA = 5:1, _Rf = 0.6): ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.56 (d, J = 2.21 Hz, 1H), 8.63 - 8.87 (m, 1H), 4.20 (br) .s., 2H); ES-LCMS m/z 232.0 (M+H).

Intermediate 9: 2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid

Step 1: 2-(4-(5-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid

Take 1,4-two containing 2-(4-bromo-2-fluorophenyl)acetic acid (300 mg, 1.287 mmol) A suspension of alkane (3 mL) and H ₂ O (1.000 mL) was added to 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (496 mg, 1.287 mmol) of 1,4-two Alkane (3 mL) in H ₂ O (1.000 mL) solution. PdCl ₂ (dppf) (94 mg, 0.129 mmol) and Cs ₂ CO ₃ (1049 mg, 3.22 mmol) were added, and the mixture was stirred at 110 ° C for 30 min under microwave irradiation. After the mixture was cooled to room temperature, the solution was concentrated, and between EA and saturated NaHCO ₃ solution was divided dissolved. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (PE / EA = 1: 1, R f = 0.5) yielded the pale yellow solid of 2- (4- (5-ethoxy-6 - ((4-methoxy-benzyloxy Oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (320 mg, 0.778 mmol, 60.4% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.93 (d, J = 1.8 Hz, 1H), 7.18-7.50 (m, 6H), 6.78-7.00 (m, 2H), 5.28-5.54 (m, 2H), 4.04-4.21 (m, 2H), 3.74-3.84 (m, 3H), 3.30- 3.38 (m, 2H), 1.32-1.52 (m, 3H); ES-LCMS m/z 412.0 (M+H).

Step 2: 2-(4-(5-Ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid

Taking 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (120 mg, 0.292 mmol) A MeOH (10 mL) suspension was added to a MeOH (10 mL) EtOAc. The mixture was stirred at 26 ° C for 2 h with hydrogen. The solution was then filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/H ₂ O as eluting solvent, acidic conditions) to yield 2-(4-(5-ethoxy-6-s. Pyridin-3-yl)-2-fluorophenyl)acetic acid (80 mg, 0.275 mmol, 94.0% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.14-7.53 (m, 5H), 4.01-4.21. m, 2H), 3.60-3.68 (m, 2H), 1.46 (s, 3H); ES-LCMS m/z 292.1 (M+H).

Intermediate 10: 4-(4-ethyl-periphere -1-ylmethyl)-3-trifluoromethyl-phenylamine

Step 1: (4-Amino-2-trifluoromethyl-phenyl)-(4-ethyl-piperidin -1-yl)-methanone

4-Amino-2-trifluoromethyl-benzoic acid (15 g, 73.1 mmol), HOBT (14.56 g, 95 mmol), EDC (16.82 g, 88 mmol), Et ₃ N (20.38 mL, 146 mmol), 1 -ethyl-piper A mixture of (8.35 g, 73.1 mmol) <RTI ID=0.0> DCM (200 mL) was added to the mixture, which was then washed with H ₂ O, 2M NaOH (2 x 150 mL) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated to give (4-amino-2-trifluoromethyl-phenyl)-(4-ethyl- -1-yl)-methanone (20 g, 65.2 mmol, 89.0% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.07 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 2.4 Hz, 1H), 6.79 (dd, J = 2.0, 8.0 Hz, 1H), 3.99 (s, 2H), 3.84-3.76 (m, 2H), 3.25-3.23 (m, 2H), 2.50-2.39 (m, 4H), 2.33 - 2.31 (m, 2H), 1.08 (t, J = 7.2 Hz, 3H); ES-LCMS m/z 302 (M+H).

Step 2: 4-(4-Ethyl-Pipeline -1-ylmethyl)-3-trifluoromethyl-phenylamine

In the presence of (4-amino-2-trifluoromethyl-phenyl)-(4-ethyl-peri L-yl) - methanone (20g, 66.4mmol) of THF (500mL) was added dropwise _{BH 3 ˙DMS (19.91mL, 199mmol)} . The mixture was then stirred at 80 ° C for 4 h. The mixture was quenched by the addition of MeOH and concentrated. The residue was purified by column chromatography (PE: EA=2:1, _Rf = 0.35) to yield 4-(4-ethyl- -1-ylmethyl)-3-trifluoromethyl-phenylamine (14 g, 46.0 mmol, 69.4% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.48 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 2.8 Hz, 1H), 6.79 (dd, J = 2.4, 8.4 Hz, 1H), 3.76 (s, 2H), 3.53 (s, 2H), 2.45-2.39 (m, 8H) ), 1.08 (t, J = 7.2 Hz, 3H); ES-LCMS m/z 288 (M+H).

Intermediate 11: 2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid

Step 1: 2-Chloro-4-ethoxypyridine

Sodium ethoxide (109.45 g, 1610 mmol) was slowly added to a mixture of 2-chloro-4-nitropyridine (170 g, 1070 mmol) in THF (2L). The mixture was stirred at 25 ° C for 12 h. LCMS and TLC (PE/EA = 5:1, _Rf = 0.6) showed that the reaction was completed. The mixture was filtered and most of the solvent of the filtrate was removed in vacuo. The residue was extracted with EtOAc (EtOAc EtOAc (EtOAc) (EtOAc) 92% yield) of solid: ¹ H NMR (400 MHz, CD ₃ OD) δ 8.15 (d, J = 6.0 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 6.91-6.89 (m, 1H) ), 4.16-4.14 (m, 2H), 1.41-1.38 (m, 3H); ES-LCMS m/z 158 (M+H).

Step 2: 5-Bromo-2-chloro-4-ethoxypyridine

Was slowly added 2-chloro-4-ethoxy pyridine (100g, 0.63mol) to H ₂ SO ₄ (500mL) in. 1-Bromopyrrolidin-2,5-dione (124.2 g, 0.70 mol) was then added to the above mixture at room temperature. The mixture was stirred at 80 ° C for 3 h. TLC (PE/EA = 10:1, _Rf = 0.5) showed that the reaction was completed. The reaction mixture was poured into ice-water (2 L) and extracted using EA (1L x 3). (1L x 2) The organic layer was washed with saturated Na ₂ CO ₃ solution, dried over sodium sulfate, and concentrated. The residue was purified by vermiculite column chromatography (PE/EA = 60:1-30:1). All the fractions containing the product (PE/EA = 10:1, R _f = 0.5) were judged by TLC to be combined and concentrated to give 5-bromo-2-chloro-4-ethoxypyridine (60.9 g, 0.26 mol, 40% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.31 (s, 1H), 7.14 (s, 1H), 4.32-4.10 (m, 2H), 1.58-1.35 (m, 3H); - LCMS m/z 237 (M+2).

Step 3: 5-Bromo-4-ethoxy-2-((4-methoxybenzyl)oxy)pyridine

Add (4-methoxyphenyl)methanol (52.6 g, 380.6) to a mixture of 5-bromo-2-chloro-4-ethoxypyridine (75 g, 317.1 mmol) in toluene (500 mL). Methyl), KOH (35.6 g, 634.3 mmol) and 18-crown-6 (8.4 g, 31.2 mmol). The reaction mixture was stirred at 120 ° C for 2 h. The mixture was partitioned between 2-methoxy-2-methylpropane (500 mL) and brine (800 mL). The organic layer was concentrated. The residue was purified by column (PE/EA = 10:1, R _f = 0.5) to yield 5-bromo-4-ethoxy-2-((4-methoxybenzyl) oxy)pyridine (72.2 g) , 221 mmol, 70% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.05 (s, 1H), 7.33 (d, J = 8.8 Hz, 2H), 6.90-6.84 (m, 2H), 6.38 ( s, 1H), 5.20 (s, 2H), 4.16-4.05 (m, 2H), 3.77 (s, 3H), 1.43 (q, J = 6.8 Hz, 3H); ES-LCMS m/z 338 (M+ 2H).

Step 4: 2-(4-Bromo-2-fluorophenyl)acetonitrile

The whole amount of NaCN (93 g, 1.90 mmol) was added once in a solution of 4-bromo-1-(bromomethyl)-2-fluorobenzene (500 g, 1.87 mol) in EtOH (2.2 L) stirred at 20 ° C. ). The reaction mixture was stirred at 60 ° C for 12 h. The solution was then concentrated, dissolved in DCM and divided between saturated NaHCO ₃ solution (1800mL) (2000mL). The same process is used for the next batch. Then the two batches are combined. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to give 2- (4-bromo-2-fluorophenyl) acetonitrile (794g, 99% ^{yield): 1 H NMR (400MHz,} CDCl 3 ) δ 7.38-7.27 (m, 3H), 3.72 (s, 2H).

Step 5: 2-(4-Bromo-2-fluorophenyl)acetic acid

Add a full amount of NaOH (2.22 L, 2.5 M, 5.56) in a solution of 2-(4-bromo-2-fluorophenyl)acetonitrile (397 g, 1.82 mol) in MeOH (500 mL). Mol) solution. The reaction mixture was stirred at 80 ° C for 5 h. The solution was then concentrated and neutralized to pH = 5 using concentrated HCl with stirring. The solution was then extracted using EA (1.5 L x 2). Repeat the same process twice. Then merge the three batches. The combined organic extracts were washed with brine, dried over sodium sulfate EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH = 5:1, R _f =0.2); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.24 (br.s., 1H), 7.12 (t, J = 7.9 Hz, 1H), 3.65 (s, 2H).

Step 6: 2-(4-Bromo-2-fluorophenyl)acetic acid methyl ester

At room temperature, the solution of 2- (4-bromo-2-fluorophenyl) acetic acid (260g, 1.13mol) of MeOH (2L) was added H ₂ SO ₄ (30mL) solution. The solution was heated to reflux overnight. The solvent was then concentrated, and between EA and saturated NaHCO ₃ solution was divided dissolved. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The same process is used for the next batch. The two batches were combined to give 2-(4-bromo-2-fluorophenyl)acetic acid methyl ester (520 g, 94%). TLC (PE/EA = 10:1, R _f = 0.7). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.25-7.20 (m, 2H), 7.14 (t, J = 8.0 Hz, 1H), 3.70 (s) , 3H), 3.62 (s, 2H).

Step 7: 2-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid methyl ester

Containing 2-(4-bromo-2-fluorophenyl)acetic acid methyl ester (260 g, 1.05 mol) and 4,4,4',4',5,5,5',5' at room temperature - 1,4-diyl-2,2'-linked (1,3,2-dioxaborolane) (320 g, 1.26 mol) of 1,4-two To the alkane (2 L) solution was added KOAc (206 g, 2.10 mol) and PdCl ₂ (dppf) (23 g, 0.03 mol). The solution was heated to reflux for 4 h under nitrogen. The solution was then filtered and the filtrate was concentrated in vacuo to give crude material. The same process is used for the next batch. The two batches were then combined and purified by vermiculite column chromatography (PE/EA = 30:1 to 10:1). All fractions containing the product (PE/EA = 10:1, R _f = 0.5) were judged by TLC to be combined and concentrated to give 2-(2-fluoro-4-(4,4,5,5-tetramethyl) -1,3,2-dioxaborolan-2-yl)phenyl)acetic acid methyl ester (560 g, 90%) as pale yellow oil: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.54 ( d, J = 7.5 Hz, 1H), 7.49 (d, J = 10.0 Hz, 1H), 7.31 - 7.26 (m, 1H), 3.73 (s, 2H), 1.34 (s, 12H), 1.27 (s, 3H) ); ES-LCMS m/z 295.2 (M+H).

Step 8: 2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid methyl ester

1,4-two in 5-bromo-4-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (175 g, 519 mmol) under nitrogen atmosphere Add 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) to a solution of alkane (1.2L) and H ₂ O (300mL) Methyl 2-phenyl)phenyl)acetate (167 g, 569 mmol), PdCl ₂ (dppf) (25 g, 5.19 mmol) and Cs ₂ CO ₃ (337 g, 1038 mmol). The mixture was refluxed for 2 h. TLC (PE/EA = 5:1, _Rf = 0.3) showed that the reaction was completed. Mixture was partitioned between EA dissolved (1L) and H ₂ O (800mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by column chromatography (PE/EA = 5:1, R _f = 0.3) to yield 5-bromo-4-ethoxy-2-((4-methoxybenzyl) oxy)pyridine (210 g, 0.49 mol, 90% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.94 (s, 1H), 7.36 (d, J = 8.8 Hz, 2H), 7.32-7.22 (m, 3H) , 6.90 (d, J = 8.8 Hz, 2H), 6.43 (s, 1H), 5.26 (s, 2H), 4.11 (d, J = 6.8 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 2H), 3.70 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H); ES-LCMS m/z 426 (M+H).

Step 9: 2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid

Containing methyl 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetate (210 g, 519 mmol ) of THF (500mL) was added a solution containing LiOH˙H ₂ O (52g, 1.23mol) of H ₂ O (700mL) was added. The mixture was stirred at 60 ° C for 10 h. TLC (PE/EA = 5:1, _Rf = 0.3) showed that the reaction was completed. The mixture was concentrated and neutralized to pH = 7.0 using 1.0 M HCl. The mixture is then filtered and the solid is washed with water and dried in vacuo to give 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2- Fluorophenyl)acetic acid (183.3 g, 0.45 mol, 93% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.94 (s, 1H), 7.41-7.28 (m, 3H), 7.24 (d, J = 9.6 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 6.44 (s, 1H), 5.26 (s, 2H), 4.11 (q, J = 6.8 Hz, 2H), 3.78 (s, 3H) ), 3.67 (s, 2H), 1.36 (t, J = 7.2 Hz, 3H); ES-LCMS m/z 412 (M+H).

Intermediate 12: 2- (4-bromo-2-fluorophenyl) - N - (3- (1,1,1- trifluoro-2-methylpropan-2-yl) iso Oxazol-5-yl)acetamide

Step 1: 2-(4-Bromo-2-fluorophenyl)acetonitrile

A solution of 4-bromo-1-(bromomethyl)-2-fluorobenzene (5.7 g, 21.27 mmol) in DMF (20 mL) wasEtOAc. The mixture was stirred at 26 ° C for 10 h. The solution was then concentrated, dissolved in EA and divided between saturated NaHCO ₃ solution (50mL) (50mL). The organic extract was washed with EtOAc (EtOAc EtOAc (EtOAc) ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.24-7.37 (m, 3 H), 3.70 (s, 2 H).

Step 2: 2-(4-Bromo-2-fluorophenyl)acetic acid

To a solution of 2-(4-bromo-2-fluorophenyl)acetonitrile (4.01 g, 18.74 mmol) MeOH (30 mL) The mixture was stirred at 100 ° C for 12 h. The mixture was then cooled to room temperature. The solution was then concentrated, and dissolved points between EA and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to give 2- (4-bromo-2-fluorophenyl) acetic acid (4.13g, 17.72mmol, 95% yield): ¹ H NMR ( 400 MHz, CDCl ₃ ) δ 7.31-7.22 (m, 2H), 7.13 (t, J = 8.05 Hz, 1H), 3.67 (s, 2H); ES-LCMS m/z 233 (M+H).

Step 3: 5,5,5-Trifluoro-4,4-dimethyl-3-oxo-valeronitrile

n- BuLi (10.58 mL, 26.5 mmol) was added to a mixture of MeOH (300 mL) EtOAc. The mixture was stirred at -30 ° C for 0.5 h. Then, 3,3,3-trifluoro-2,2-dimethylpropionic acid methyl ester (3 g, 17.63 mmol) was added dropwise to the mixture. Aqueous NH ₄ Cl mixture quenched using DCM / MeOH: extraction (10 1,30mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (PE/EA = 8:1). All the fractions containing the product (PE/EA = 5:1, R _f = 0.5) were judged by TLC to be combined and concentrated to give 5,5,5-trifluoro-4,4-dimethyl as a pale yellow oil. pentyl-3-oxo-carbonitrile (1g, 5.30mmol, 30% ^{yield): 1 H NMR (400MHz,} CDCl 3) δ 3.79 (s, 2H), 1.41 (s, 6H).

Step 4: 3-(1,1,1-Trifluoro-2-methylpropan-2-yl) Azole-5-amine

Water (30 mL) containing 5,5,5-trifluoro-4,4-dimethyl-3-oxovaleronitrile (1 g, 5.58 mmol) and hydroxylamine hydrochloride (0.407 g, 5.86 mmol) NaOH (0.447 g, 11.16 mmol) was added to the mixture. The mixture was then stirred at 100 ° C for 3 h. After cooling to room temperature, the mixture was extracted with DCM (50 mL×3). The organic layer was dried over sodium sulfate, filtered and concentrated to give 3-(1,1,1-trifluoro-2-methylpropan-2-yl) Imidazole-5-amine (700 mg, 3.39 mmol, 61% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.17 (s, 1H), 4.41 (s, 2H), 1.49 (s, 6H); LCMS m/z 195 (M+H).

Step 5: 2- (4-bromo-2-fluorophenyl) - N - (3- (1,1,1- trifluoro-2-methylpropan-2-yl) iso Oxazol-5-yl)acetamide

Add 3-(1,1,1-trifluoro-2-methylpropan-2-) to a mixture of 2-(4-bromo-2-fluorophenyl)acetic acid (360 mg, 1.545 mmol) in DCM (50 mL) Base) Zyrid-5-amine (300 mg, 1.545 mmol), HATU (881 mg, 2.317 mmol) and triethylamine (0.645 mL, 4.63 mmol). The mixture was then stirred at 25 ° C for 12 h. The mixture was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated to give a yellow oil of 2- (4-bromo-2-fluorophenyl) - N - (3- (1,1,1- Trifluoro-2-methylpropan-2-yl)iso Oxazol-5-yl)acetamide (600 mg, 1.1 mmol, 71% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 (d, J = 6.8 Hz, 1H), 7.34-7.29 (m, 1H) ), 7.21 (s, 1H), 6.64 (d, J = 6.8 Hz, 1H), 6.43 (s, 1H), 3.75 (s, 2H), 1.52 (s, 6H); ES-LCMS m/z 409 ( M+H).

Preparation method of the compound of the invention

Example 1: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (6- (2- hydroxy Propane-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide

Step 1: 2-Chloro-5-nitro-3-(trifluoromethyl)pyridine

Nitric acid (1.644 mL, 36.8 mmol) and H ₂ SO ₄ (12.03 g, 123 mmol) were added to a mixture of 3-(trifluoromethyl)pyridin-2-ol (2 g, 12.26 mmol). The mixture was then stirred at 25 ° C for 16 h. The mixture was then warmed to 60 ° C over 5 hours, cooled and added to 150 g of ice. Using a mixture of EA (2 x 100mL) and extracted using H ₂ O (100mL), dried the organic layer was produced. The combined organic extracts were washed with EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ¹ H NMR (400 MHz, CD ₃ OD) δ 8.91 (d, J = 2.43 Hz, 1H), 9.42 (d, J = 2.43 Hz, 1H); ES-LCMS m/z 209.0 (M+H).

Step 2: 2-Chloro-5-nitro-3-(trifluoromethyl)pyridine

3- (trifluoromethyl) pyridin-2-ol (2g, 9.61mmol) was added a mixture of SOCl ₂ (21.04mL, 288mmol) and DMF (0.074mL, 0.961mmol) in 5-nitro. The mixture was then stirred at 80 ° C for 16 h. The mixture was concentrated, extracted with EA (2 x 100mL), washed with H ₂ O (100mL), the organic layer was produced. The combined organic extracts were washed with EtOAcqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ¹ H NMR (400 MHz, CD ₃ OD) δ 8.91 (d, J = 2.43 Hz, 1H), 9.42 (d, J = 2.43 Hz, 1H).

Step 3: 6-Chloro-5-(trifluoromethyl)pyridin-3-amine

A full amount of iron (2.465 g, 44.1 mmol) was added in one portion to a mixture of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (2 g, 8.83 mmol) in acetic acid (10 mL). The mixture was stirred at 80 ° C for 15 min. The mixture was filtered and concentrated, then washed with aqueous NaOH and extracted with EtOAc. The crude product was purified by column chromatography (PE/EA = 5:1). All the fractions containing the product (PE/EA = 8:1, _Rf = 0.6) were judged by TLC to be combined and concentrated to give 6-chloro-5-(trifluoromethyl)pyridin-3-amine as a yellow solid. 1g, 4.58mmol, 51.9% ^{yield): 1 H NMR (400MHz,} CD 3 OD) δ 8.06 (s, 1H), 7.86 (d, J = 8.60Hz, 1H), 7.53 (d, J = 8.60Hz, 1H), 7.46-7.26 (m, 5H), 4.16-4.11 (m, 2H), 3.81 (s, 2H), 1.47 (t, J = 6.62 Hz, 3H); ES-LCMS m/z 197.0 (M+ H).

Step 4: 1-(5-Amino-3-(trifluoromethyl)pyridin-2-yl)ethanone

Add 6-chloro-5-(trifluoromethyl)pyridin-3-amine to a mixture of 6-chloro-5-(trifluoromethyl)pyridin-3-amine (200 mg, 1.018 mmol) in MeOH (3 mL) (200 mg, 1.018 mmol), NaHCO ₃ (171 mg, 2.035 mmol) and PdCl ₂ (dppf) (74.5 mg, 0.102 mmol). Mask N ₂ mixture gas at 110 deg.] C and the microwave was stirred 30min. The reaction residue was then filtered and the solid was washed with MeOH. Then, 6 M HCl was added to the solution, and the mixture was stirred at room temperature for 1 hour and then concentrated to give a crude product. The crude product was purified by preparative TLC (PE / EA = 1: 1, R f = 0.6) yielded the pale yellow solid of 1- (5-amino-3- (trifluoromethyl) pyridin-2-yl) acetate Ketone (120 mg, 0.500 mmol, 49.1% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.10 (d, J = 2.43 Hz, 1H), 7.30 (d, J = 2.43 Hz, 1H), 2.56 ( s, 3H); ES-LCMS m/z 205.0 (M+H).

Step 5: N- (6-Ethyl-5-(trifluoromethyl)pyridin-3-yl)-2-(4-bromo-2-fluorophenyl)acetamide

Add 2-(4-bromo-2-fluorophenyl)acetic acid (125 mg, 0.536 mmol) to a mixture of 2-(4-bromo-2-fluorophenyl)acetic acid (125 mg, 0.536 mmol) , EDC (123mg, 0.644mmol), HOBt (99mg, 0.644mmol) and _{Et 3 N (0.150mL, 1.073mmol)} . The mixture was stirred at 25 ° C for 16 h. The reaction mass is then concentrated to residue to give a crude product which was purified by preparative TLC (PE / EA = 1: 1, R f = 0.6) yielded the pale yellow solid of N - (6- acetyl-5- (trifluoromethyl Pyridin-3-yl)-2-(4-bromo-2-fluorophenyl)acetamide (120 mg, 0.243 mmol, 45.4% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 9.00 ( d, J = 1.5 Hz, 1H), 8.60 (d, J = 1.5 Hz, 1H), 8.13 (d, J = 2.5 Hz, 2H), 7.33 (s., 1H), 3.85 (s, 2H), 2.66 (s, 3H); ES-LCMS m/z 418.9 (M+H).

Step 6: N- (6-Ethyl-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-((4-methoxyphenyl)) Oxy)pyridin-3-yl)-2-fluorophenyl)acetamide

In the presence of 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane Pentane-2-yl)pyridine (100 mg, 0.260 mmol) of 1,4-two Dioxane (3mL) and H ₂ O (1mL) was added a mixture of N - (6-acetyl-5- (trifluoromethyl) pyridin-3-yl) -2- (4-bromo-2-fluorophenyl Ethylamine (120 mg, 0.286 mmol), Cs ₂ CO ₃ (169 mg, 0.519 mmol) and PdCl ₂ (dppf) (18.99 mg, 0.026 mmol). Mask N ₂ mixture gas at 110 deg.] C and the microwave was stirred 30min. The reaction residue was then filtered, and the filtrate was concentrated to give a crude material, which was purified by preparative TLC (PE/EA = 1:1, _Rf = 0.6) to give N- (6-ethyiyl-5- Trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorobenzene Ethylamine (100 mg, 0.100 mmol, 38.7% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 9.02 (s, 1H), 8.62 (s, 1H), 8.13 (d, J = 2.0 Hz , 2H), 7.42 (d, J = 9.0 Hz, 4H), 7.33 (d, J = 2.5 Hz, 2H), 6.94 (s, 1H), 5.39 (s, 2H), 4.15-4.09 (m, 2H) , 3.91 (s, 2H), 2.03 (s, 3H), 1.26 (t, J = 7.0 Hz, 3H); ES-LCMS m/z 598.1 (M+H).

Step 7: 2- (4- (5-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (6- ( 2-hydroxypropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide

Containing N- (6-ethenyl-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)) To a mixture of oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (100 mg, 0.167 mmol) in THF (10 mL) EtOAc (EtOAc) The mixture was stirred at 0 ° C under N ₂ atmosphere for 2 h. The mixture was then added to the H ₂ O, and extracted with EA. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (DCM / MeOH = 15: 1 , R f = 0.6), to yield a yellow solid of 2- (4- (5-ethoxy-6 - ((4-methoxybenzyl ) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (6- (2- hydroxy-2-yl) -5- (trifluoromethyl) pyridin-3-yl) acetyl amine (70 mg, 0.086 mmol, 51.1% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.87 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.09 (d) , J = 2.4 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.44 - 7.40 (m, 3H), 7.29 (d, J = 2.4 Hz, 1H), 6.88 (s, 2H) 6.78 ( d, J = 2.4 Hz, 1H), 5.35 (s, 2H), 4.17-4.11 (m, 2H), 3.83 (s, 2H), 3.77 (s, 3H), 1.59 (s, 6H), 1.41 (t , J = 7.1 Hz, 3H); ES-LCMS m/z 494.2 (M-PMB+H).

Step 8: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (6- (2- hydroxy Propane-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide

Containing 2- (4- (5-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (6- (2 A mixture of hydroxypropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide (70 mg, 0.114 mmol) in MeOH (10 mL) H ₂ mixture at 25 deg.] C and stirred for gas mask 16h. The reaction residue was then filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/H ₂ O as eluting solvent, basic conditions) to yield 2-(4-(5-ethoxy-6-s-oxyl-1,6-dihydro) as a white solid. pyridin-3-yl) -2-fluorophenyl) - N - (6- (2- hydroxy-2-yl) -5- (trifluoromethyl) pyridin-3-yl) acetyl amine (5.71mg , 0.011 mmol, 10.9% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.90 (s, 1H), 8.48 (s, 1H), 7.48-7.43 (m, 1H), 7.40-7.32 (m, 3H), 7.26 (d, J = 2.01 Hz, 1H), 4.15 (m, 2H), 3.86 (s, 2H), 1.62 (s, 6H), 1.49 (t, J = 7.03 Hz, 3H); LCMS m/z 494.2 (M+H).

Example 2: N- (6-ethoxy-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-o-oxy-1,6-di Hydropyridin-3-yl)-2-fluorophenyl)acetamide hydrochloride

Step 1: 2-Chloro-5-nitro-3-(trifluoromethyl)pyridine

H ₂ SO ₄ (12.03 g, 123 mmol) was added to a mixture of 3-(trifluoromethyl)pyridin-2-ol (2 g, 12.26 mmol) and nitric acid (1.644 mL, 36.8 mmol). The mixture was then stirred at 25 ° C for 16 h. The mixture was then warmed to 60 ° C over 5 hours, cooled and added to 150 g of ice. Using a mixture of EA (2 x 100mL) and extracted using H ₂ O (100mL), dried the organic layer was produced. The combined organic extracts were washed with brine, dried over sodium sulfatessssssssssssssssssssssssssssssss Yield: ¹ H NMR (400 MHz, CD ₃ OD) δ 8.91 (d, J = 2.43 Hz, 1H), 9.42 (d, J = 2.43 Hz, 1H); ES-LCMS m/z 209.0 (M+H ).

Step 2: 2-Chloro-5-nitro-3-(trifluoromethyl)pyridine

In a solution of 5-nitro-3- (trifluoromethyl) pyridin-2-ol (2g, 9.61mmol) and SOCl ₂ (21.04mL, 288mmol) was added a mixture of DMF (0.074mL, 0.961mmol). The mixture was then stirred at 80 ° C for 16 h. The mixture was concentrated, extracted with EA (2 x 100mL), washed with H ₂ O (100mL), the organic layer was produced. The combined organic extracts were washed with brine, dried over sodium sulfatesssssssssssssssssssssssssssss Rate: ¹ H NMR (400 MHz, CD ₃ OD) δ 8.91 (d, J = 2.43 Hz, 1H), 9.42 (d, J = 2.43 Hz, 1H).

Step 3: 2-Ethoxy-5-nitro-3-(trifluoromethyl)pyridine

Add a mixture of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (500 mg, 2.207 mmol) in THF (10 mL) EtOAc (EtOAc: EtOAc. . The mixture was then stirred at 0 ° C for 30 min then warmed to room temperature and stirred for 16 h. The mixture was added to H ₂ O and extracted using EA (2 x 50mL), the organic layer was produced. The combined organic extracts were washed with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHH , 20.7% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 9.27 (d, J = 2.5 Hz, 1H), 8.75 (d, J = 2.5 Hz, 1H), 4.67 (m, 2H), 1.47 (t, J = 7.0 Hz, 3H).

Step 4: 6-Ethoxy-5-(trifluoromethyl)pyridin-3-amine

Add tin(II) chloride dihydrate (459 mg, 2.033 mmol) to a mixture of 2-ethoxy-5-nitro-3-(trifluoromethyl)pyridine (120 mg, 0.508 mmol) in EA (10 mL) ). The mixture was stirred at 50 ° C for 16 h. The solution was then dissolved between EA and a saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (PE / EA = 4: 1, R f = 0.6) was generated as a pale yellow oil of 6-ethoxy-5- (trifluoromethyl) pyridin-3-amine (80 mg of , 0.310 mmol, 61.1% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 6.27 (d, J = 2.5 Hz, 1H), 5.86 (d, J = 3.0 Hz, 1H), 2.81 (m, 2H) ), 0.17 (t, J = 7.0 Hz, 3H); ES-LCMS m/z 207.1 (M+H).

Step 5: 2- (4-bromo-2-fluorophenyl) - N - (6- ethoxy-5- (trifluoromethyl) pyridin-3-yl) acetyl amine

Add 6-ethoxy-5-(trifluoromethyl)pyridin-3-amine to a mixture of 2-(4-bromo-2-fluorophenyl)acetic acid (90 mg, 0.386 mmol) in DCM (10 mL) 88 mg, 0.425 mmol), DIEA (0.135 mL, 0.772 mmol) and HATU (220 mg, 0.579 mmol). The mixture was stirred at 25 ° C for 16 h. The mixture was diluted with water and extracted with DCM. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (PE / EA = 1: 1, R f = 0.6) was generated as a pale yellow oil of 2- (4-bromo-2-fluorophenyl) - N - (6- ethoxy 5-H-(trifluoromethyl)pyridin-3-yl)acetamide (120 mg, 0.228 mmol, 59.0% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.49 (d, J = 2.0 Hz , 1H), 8.27 (d, J = 2.5 Hz, 1H), 7.39-7.34 (m, 3H), 4.47 (m, 2H), 1.21 (t, J = 6.5 Hz, 3H); ES-LCMS m/z 421.0 (M+H).

Step 6: N- (6-ethoxy-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-((4-methoxyphenyl)) Oxy)pyridin-3-yl)-2-fluorophenyl)acetamide

In the presence of 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane Pentane-2-yl)pyridine (100 mg, 0.260 mmol) of 1,4-two Dioxane (3mL) and H ₂ O (1mL) was added a mixture of 2- (4-bromo-2-fluorophenyl) - N - (6- ethoxy-5- (trifluoromethyl) pyridin-3-yl Ethylamine (120 mg, 0.286 mmol), Cs ₂ CO ₃ (169 mg, 0.519 mmol) and PdCl ₂ (dppf) (18.99 mg, 0.026 mmol). The mixture was stirred under a nitrogen atmosphere at 110 ° C for 30 min. The reaction residue was then filtered, and the filtrate was concentrated to give a crude material which was purified by preparative TLC (PE: EA = 1:1, _Rf = 0.6) to give N- (6-ethoxy-5- Trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorobenzene Acetamide (50 mg, 0.071 mmol, 27.3% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.51 (d, J = 2.5 Hz, 1H), 8.29 (d, J = 2.5 Hz, 1H) ), 7.97 (d, J = 2.0 Hz, 1H), 7.52 - 7.35 (m, 6H), 6.93 (d, J = 8.5 Hz, 2H), 5.39 (s, 2H), 4.47 (m, 2H), 4.17 (m, 2H), 3.78-3.85 (m, 5H), 1.42-1.47 (m, 3H), 1.38-1.42 (m, 3H); ES-LCMS m/z 600.1 (M+H).

Step 7: N- (6-ethoxy-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-o-oxy-1,6-di Hydropyridin-3-yl)-2-fluorophenyl)acetamide hydrochloride

Containing N- (6-ethoxy-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)) TFA (0.701 mL, 9.10 mmol) was added to a mixture of EtOAc &lt;RTI ID=0.0&gt;&gt; The mixture was stirred at 25 ° C for 2 h. The reaction residue was then added to NaOH (2.5 m, 3 mL) and concentrated. The crude product was purified by preparative HPLC (MeCN / H ₂ O as the eluent, basic conditions), a white solid of N - (6- ethoxy-5- (trifluoromethyl) pyridin-3-yl) - 2-(4-(5-Ethoxy-6-oxooxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide hydrochloride (15.66 mg, 0.030 mmol, 49.8% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.50 (s, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.49-7.41 (m, 1H), 7.40-7.31 (m) , 3H), 7.26 (d, J = 2.0 Hz, 1H), 4.47 (m, 2H), 4, 15 (m, 2H), 3.82 (s, 2H), 1.49 (t, J = 7.0 Hz, 3H) , 1.40 (t, J = 7.0 Hz, 3H); ES-LCMS m/z 480.2 (M+H).

Example 3: 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (4- (3- hydroxy -2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

Step 1: 3-(4-(2-(4-Bromo-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoic acid Base ester

3-(4-Amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoic acid ethyl ester (200 mg, 0.691 mmol) was added to 2-(4-bromo-2) -Fluorophenyl)acetic acid (161 mg, 0.691 mmol), HATU (315 mg, 0.830 mmol), EtOAc (EtOAc) After the reaction mixture was stirred at room temperature for 2h, the solution was dissolved between DCM and sub H ₂ O. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative _{TLC (DCM, R f = 0.5} ) was generated as a pale yellow oil of 3- (4- (2- (4-bromo-2-fluorophenyl) amino-acetylamino) -2- (Trifluoromethyl)phenyl)-2,2-dimethylpropanoic acid ethyl ester (320 mg, 0.571 mmol, 83.0% yield): ¹ H NMR (400 MHz, MeOH - d ₄ ) δ 7.94 (d, J = 1.54 Hz, 1H), 7.68 (d, J = 8.38 Hz, 1H), 7.27-7.36 (m, 2H), 7.22 (d, J = 8.38 Hz, 1H), 6.90-6.97 (m, 1H), 4.09-4.18(m,2H), 3.74(s,2H),3.07(s,2H),1.20-1.25(m,3H),1.15(s,6H);ES-LCMS m/z 504(M+H ).

Step 2: 3-(4-(2-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene) Ethylamino)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoic acid ethyl ester

PdCl ₂ (dppf) (23.21 mg, 0.032 mmol) was added to 3-(4-(2-(4-bromo-2-fluorophenyl)acetamido)-2-(trifluoromethyl)benzene Ethyl 2,2-dimethylpropionic acid ethyl ester (320 mg, 0.635 mmol), KOAc (187 mg, 1.904 mmol) and 4,4,4',4',5,5,5',5'- Octamethyl-2,2'-linked (1,3,2-dioxaborolane) (193 mg, 0.761 mmol) of 1,4-two In a solution of alkane (10 mL). The reaction mixture was stirred at 100 ° C for 8 h. The solution was then concentrated, and dissolved points between EA and H ₂ O. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (PE / EA = 5: 1, R f = 0.6) was generated as a pale yellow oil of 3- (4- (2- (2-fluoro-4- (4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylamino)-2-(trifluoromethyl)phenyl)-2,2- Ethyl dimethylpropionate (300 mg, 0.490 mmol, 77% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.94 (s, 1H), 7.68 (d, J = 8.60 Hz, 1H), 7.50 (d, J = 7.50 Hz, 1H), 7.33-7.41 (m, 2H), 7.22 (d, J = 8.60 Hz, 1H), 4.12-4.15 (m, 2H), 3.78 (s, 2H), 3.07 (s, 2H), 1.33 (s, 12H), 1.22 (d, J = 1.54 Hz, 3H), 1.15 (s, 6H); ES-LCMS m/z 552 (M+H).

Step 3: 3-(4-(2-(4-(6-(Benzyloxy)-4-ethoxypyridin-3-yl)-2-fluorophenyl)ethinyl)-2- (trifluoromethyl)phenyl)-2,2-dimethylpropionic acid ethyl ester

PdCl ₂ (dppf) (13.27 mg, 0.018 mmol), 4-(benzyloxy)-2-ethoxy-1-iodobenzene (0.131 mL, 0.399 mmol), 3-(4-(2-) (2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamido)-2-( Trifluoromethyl)phenyl)-2,2-dimethylpropanoic acid ethyl ester (0.121 mL, 0.363 mmol) and Cs ₂ CO ₃ (355 mg, 1.088 mmol) of H ₂ O (1 mL) and 1,4 -two The reaction mixture of the alkane (3 mL) was stirred at 100 ° C for 2 h. The solution was then concentrated, and dissolved between DCM and sub H ₂ O. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. The crude product was purified by column chromatography (PE/EA = 5:1). All the fractions containing the product (PE/EA = 2:1, R _f = 0.6) were judged by TLC to be combined and concentrated to give 3-(4-(2-(4'-)) Baseoxy)-2'-ethoxy-3-fluoro-[1,1'-biphenyl]-4-yl)ethylamino)-2-(trifluoromethyl)phenyl)-2,2 -ethyl dimethylpropionate (100 mg, 0.147 mmol, 40.6% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.93-7.98 (m, 2H), 7.71 (dd, J = 8.49, 1.87 Hz, 1H), 7.42-7.46 (m, 2H), 7.32-7.39 (m, 3H), 7.25-7.31 (m, 3H), 7.23 (d, J = 8.60 Hz, 1H), 6.48 (s, 1H) , 5.35 (s, 2H), 4.10-4.17 (m, 4H), 3.79 (s, 2H), 3.07 (s, 2H), 2.00 (s, 2H), 1.23 (dd, J = 7.17, 0.88 Hz, 6H ), 1.15 (s, 6H); ES-LCMS m/z 653 (M+H).

Step 4: 2- (4- (6- (benzyl oxy) -4-ethoxy-pyridin-3-yl) -2-fluorophenyl) - N - (4- (3- hydroxy-2,2 - Dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

Add LAH (17.45 mg, 0.460 mmol) to 3-(4-(2-(4-(6-(benzyloxy))-4-ethoxypyridin-3-yl)-2-fluorophenyl) A solution of ethyl acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (100 mg, 0.153 mmol) in THF (5 mL). The reaction mixture was stirred at 25 ° C for 1 h. The reaction was then extracted with EA (50 mL), washed with water and NaOH solution and dried over sodium sulfate. The combined organic extracts were purified by preparative TLC (PE/EA = 2:1, _Rf = 0.4) to yield 2-(4-(6-(phenylmethyloxy)) oxy-3-yl) -2-fluorophenyl) - N - (4- (3- hydroxy-2,2-dimethylpropyl) -3- (trifluoromethyl) phenyl) acetyl Amine (20 mg, 0.032 mmol, 20.9% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.94-8.03 (m, 2H) 7.77 (d, J = 8. s Hz, 1H) 7.46 (t, J = 7.53) Hz,3H)7.36-7.43(m,3H)7.27-7.35(m,3H)6.52(s,1H)5.38(s,2H)3.83(s,2H)2.81(s,2H)2.03(s,4H) 1.40 (t, J = 6.78 Hz, 3H) 1.26 (t, J = 7.28 Hz, 3H) 0.82 - 0.90 (m, 6H); ES-LCMS m/z 611 (M+H).

Step 5: 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (4- (3- hydroxy -2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

A mixture of 2- (4- (6- (benzyl oxy) -4-ethoxy-pyridin-3-yl) -2-fluorophenyl) - N - (4- (3- hydroxy-2,2 Reaction mixture of dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (20 mg, 0.033 mmol) and Pd/C (3.49 mg, 0.033 mmol) in MeOH (3 mL) ₂ Stir under the air for 20 min. The solution was then concentrated, and purified by preparative HPLC (MeCN / H ₂ O as the eluent, acidic conditions), a white solid of 2- (4- (4-ethoxy-6-oxo-1,6 - dihydro-pyridin-3-yl) -2-fluorophenyl) - N - (4- (3- hydroxy-2,2-dimethylpropyl) -3- (trifluoromethyl) phenyl) acetate Indoleamine (11.88 mg, 0.022 mmol, 67.7% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.95 (d, J = 1.98 Hz, 1H), 7.79 (s, 1H), 7.71 (dd, J = 8.49, 1.87 Hz, 1H), 7.40-7.46 (m, 2H), 7.25-7.32 (m, 2H), 6.37 (s, 1H), 4.24 (q, J = 6.84 Hz, 2H), 3.82 (s, 2H), 3.35 (br.s., 2H), 2.77 (s, 2H), 1.41 (t, J = 6.95 Hz, 3H), 0.83 (s, 6H); ES-LCMS m/z 521 (M+H ).

Example 4: (2,3-difluorophenyl 4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)) 2- - N - (4- ( 2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamide

Step 1: (4-Bromo-2,3-difluorophenyl)methanol

Under N ₂ gas and the mask containing 0 ℃ of 4-bromo-2,3-difluoro-benzoic acid (650mg, 2.74mmol) of THF (5mL) was added in a total amount of BH ₃ ˙DMS (1.371mL, 13.71mmol) . The reaction mixture was stirred at 67 ° C for 2 h. MeOH (5 mL) was added to the solution at room temperature. The solution was then stirred at room temperature for 30 min. The solution was concentrated in vacuo to give a crude material. The resulting (4-bromo-2,3-difluorophenyl)methanol (600 mg, 1.449 mmol, 63.8% yield) was used in the next step without further purification. TLC (PE / EA = 2: 1, R f 0.6): 1 H NMR (400mHz, CDCl 3) δ 7.37-7.28 (m, 1H), 7.12 (t, J = 7.4Hz, 1H), 4.76 (d, J = 5.2 Hz, 2H), 3.70 (s, 1H).

Step 2: 1-Bromo-4-(bromomethyl)-2,3-difluorobenzene

The whole amount of PBr ₃ (0.634 mL, 6.73 mmol) was added in one portion to a solution of (4-bromo-2,3-difluorophenyl)methanol (500 mg, 2.42 mmol) in DCM (10 mL). ). The reaction mixture was stirred at 10 ° C for 2 h. The solution was then concentrated, and dissolved in divided between DCM and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (PE / EA = 10: 1, R f 0.6) was generated as a pale yellow oil of 1-bromo-4- (bromomethyl) -2,3-difluorobenzene (330 mg of, 1.154mmol, 51.5% yield): ¹ H NMR (400MHz, CDCl ₃ ) δ 7.30 (ddd, J = 2.0, 6.0, 8.2 Hz, 1H), 7.11-7.03 (m, 1H), 4.46 (s, 2H) .

Step 3: 2-(4-Bromo-2,3-difluorophenyl)acetonitrile

Adding a full amount of NaCN (73.5 mg) in a solution of 1-bromo-4-(bromomethyl)-2,3-difluorobenzene (330 mg, 1.154 mmol) in EtOH (10 mL) with stirring at 0 ° C , 1.500mmol). The reaction mixture was stirred at 10 ° C for 12 h. The solution was then concentrated, and dissolved points between EA and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The obtained 2-(4-bromo-2,3-difluorophenyl)acetonitrile was used in the next step without further purification. TLC (PE/EA = 5:1, _Rf 0.6): ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39 (ddd, J = 1.8, 6.1, 8.2 Hz, 1H), 7.15 (t, J = 6.8 Hz, 1H), 3.78 (s, 2H).

Step 4: 2-(4-Bromo-2,3-difluorophenyl)acetic acid

Take compound 2- (4-bromo-2,3-difluorophenyl) acetonitrile (200mg, 0.690mmol) was dissolved in H ₂ O (1mL), was added at 20 ℃ a total amount of H ₂ SO ₄ (1mL). The reaction mixture was stirred at 100 ° C for 1 h. The solution is then partitioned between EA and H ₂ O. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The obtained 2-(4-bromo-2,3-difluorophenyl)acetic acid (180 mg, 0.287 mmol, 41.6% yield) was used for the next step without further purification. TLC (PE/EA = 2:1, _Rf 0.6): ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.27-7.20 (m, 1H), 6.92 - 6.85 (m, 1H), 3.65 (s, 2H); ES-LCMS m/z 250.0 (M+H).

Step 5: N- (4-(2-(Benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2,3-difluorophenyl) Acetamine

4-(2-(Benzyloxy)ethoxy)-3-(trifluoromethyl)aniline (20 mg, 0.064 mmol), 2-(4-bromo-)-mixed with nitrogen gas at 20 ° C A solution of 2,3-difluorophenyl)acetic acid (48.4 mg, 0.077 mmol) and DIEA (0.034 mL, 0.193 mmol) in DCM (3 mL) The reaction mixture was stirred at 20 ° C for 2 h. The solution was then dissolved in divided between DCM and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (PE / EA = 5: 1, R f 0.3) was generated as a pale yellow solid of N - (4- (2- (phenylmethyl) ethoxy) -3- (trifluoromethyl Methyl)phenyl)-2-(4-bromo-2,3-difluorophenyl)acetamide (12 mg, 0.019 mmol, 29.9% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.69- 7.59 (m, 2H), 7.36-7.24 (m, 6H), 7.05 (t, J = 7.3 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 4.64 (s, 2H), 4.20 (t) , J = 4.4 Hz, 2H), 3.86 (t, J = 4.8 Hz, 2H), 3.71 (s, 2H); ES-LCMS m/z 546.0 (M+H).

Step 6: N- (4-(2-(Benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-(( 4-methoxybenzyloxy)pyridin-3-yl)-2,3-difluorophenyl)acetamide

3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1, which is stirred under nitrogen at 20 ° C, 3,2-dioxaborolan-2-yl)pyridine (8.49 mg, 0.022 mmol), N- (4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl) Phenyl)-2-(4-bromo-2,3-difluorophenyl)acetamide (12 mg, 0.022 mmol) and Cs ₂ CO ₃ (17.96 mg, 0.055 mmol) 1,4-di A full amount of PdCl ₂ (dppf) (0.807 mg, 1.102 μmol) was added in one portion to a solution of alkane (6 mL) and H ₂ O (2 mL). The reaction vessel was heated at 110 ° C for 3 h. The solution was then concentrated, and dissolved points between EA and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (PE / EA = 2: 1, R f = 0.6) yielded the brown solid of N - (4- (2- (phenylmethyl) ethoxy) -3- (trifluoromethyl Methyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2,3-difluorophenyl) Acetamide (10 mg, 0.012 mmol, 52.7% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82 (d, J = 3.0 Hz, 1H), 7.66-7.50 (m, 2H), 7.41 - 7.34 m, 2H), 7.29-7.07 (m, 8H), 6.95-6.80 (m, 3H), 5.39 (d, J = 4.9 Hz, 2H), 4.57 (d, J = 5.0 Hz, 2H), 4.14 (d) , J = 4.0 Hz, 2H), 4.09-3.96 (m, 2H), 3.84 - 3.66 (m, 7H), 1.38 (q, J = 6.4 Hz, 3H); ES-LCMS m/z 723.1 (M+H ).

Step 7: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2,3-difluorophenyl) - N - (4- ( 2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamide

Containing N- (4-(2-(benzylideneoxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-) in a nitrogen atmosphere at 20 ° C A solution of ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2,3-difluorophenyl)acetamide (10 mg, 0.014 mmol) in MeOH (3 mL) A full amount of Pd/C (0.147 mg, 1.384 μmol) was added at once. The solution was stirred under H ₂ atmosphere. The reaction mixture was stirred at 10 ° C for 12 h. The mixture was filtered and the filtrate was concentrated in vacuo to give crude material. The crude product was purified by preparative HPLC (MeCN/H ₂ O as eluting solvent, acidic conditions) to yield 2-(4-(5-ethoxy-6-s. pyridin-3-yl) -2,3-difluorophenyl) - N - (4- (2- hydroxyethoxy) -3- (trifluoromethyl) phenyl) acetyl amine (3.17mg, 6.19 Μmol, 44.7% yield). TLC (DCM / MeOH = 5: 1, R f = 0.4): 1 H NMR (400MHz, CD 3 OD) δ 7.88 (d, J = 2.4Hz, 1H), 7.75 (dd, J = 2.2,8.8Hz, 1H), 7.37-7.12 (m, 5H), 4.20-4.07 (m, 4H), 3.90 (t, J = 5.0 Hz, 2H), 3.85 (s, 2H), 1.48 (t, J = 7.0 Hz, 3H) ); ES-LCMS m/z 513.2 (M+H).

Example 5: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (4- (3- hydroxy -2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

Step 1: 3-(4-Amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropan-1-ol

Add 3-(4-Amino-2-(trifluoromethyl)phenyl)- to a mixture of 2-(4-bromo-2-fluorophenyl)acetic acid (6 g, 25.7 mmol) in DCM (50 mL) 2,2-dimethyl-propionic acid ethyl ester (7.45g, 25.7mmol), HATU ( 12.73g, 33.5mmol) and _{Et 3 N (10.74mL, 77mmol)} . The mixture was then stirred at 25 ° C for 12 h. The mixture was washed with brine and saturated NaHCO ₃ solution. The organic layer was dried over MgSO4, filtered and concentrated to afford 3-(4-(4-(4-bromo-2-fluorophenyl)ethylamino)-2-(trifluoromethyl) Ethyl phenyl)-2,2-dimethylpropanoic acid ethyl ester (12 g, 19.99 mmol, 78.0% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ: 7.94 (d, J = 2.0 Hz, 1H ), 7.67 (d, J = 8.4 Hz, 1H), 7.36-7.25 (m, 3H), 7.22 (d, J = 8.4 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.73 (s) , 2H), 3.07 (s, 2H), 1.22 (t, J = 7.2 Hz, 3H), 1.15 (s, 6H); ES-LCMS m/z 504 (M).

Step 2: 3-(4-(2-(4-(5-ethoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl) Ethylamino)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoic acid ethyl ester

3-oxo-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2 under nitrogen atmosphere -dioxaborolan-2-yl)pyridine (4.58 g, 11.90 mmol) and 3-(4-(2-(4-bromo-2-fluorophenyl)acetamido)-2-( Ethyl trifluoromethyl)phenyl)-2,2-dimethylpropanoate (6 g, 11.90 mmol) in H ₂ O (1 mL) and 1,4- Cs ₂ CO ₃ (7.75 g, 23.79 mmol) and PdCl ₂ (dppf) (0.435 g, 0.595 mmol) were added to a mixture of hexanes (3 mL). The mixture was then stirred and irradiated in a microwave oven at 120 ° C for 30 min. The mixture was concentrated and extracted with EA. The combined organic layers were concentrated. The crude product was purified by column chromatography (PE/EA = 5:1). All fractions containing the product (PE/EA = 2:1, _Rf = 0.45) were judged by TLC to be combined and concentrated to give 3-(4-(4-(5-ethoxy)- as a yellow solid. 6-((4-Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)ethylamino)-2-(trifluoromethyl)phenyl)-2,2- Ethyl dimethylpropionate (4.5 g, 4.63 mmol, 38.9% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ: 7.98-7.93 (m, 2H), 7.70 (d, J = 6.8 Hz) , 1H), 7.46-7.35 (m, 6H), 7.23 (d, J = 8.6 Hz, 1H), 6.90 (d, J = 8.6 Hz, 2H), 5.36 (s, 2H), 4.18-4.10 (m, 4H), 3.83-3.75 (m, 5H), 3.09-3.05 (m, 2H), 1.41 (t, J = 7.2 Hz, 3H), 1.24 (d, J = 1.8 Hz, 9H); ES-LCMS m/ z 563 (M-120).

Step 3: 2- (4- (5-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (4- ( 3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

3-(4-(2-(4-(5-ethoxybenzyl)oxy)pyridin-3-yl)-2-fluoro) was cooled to 0 °C Phenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoic acid ethyl ester (3.5 g, LAH (0.389 g, 10.25 mmol) was added portionwise in a mixture of THF (200 mL).

The mixture was stirred at 0 ° C for 30 min. The mixture was quenched with 15% aqueous NaOH (10 mL). The mixture was dehydrated over sodium sulfate. The mixture was filtered and the filtrate was concentrated. The residue was purified by vermiculite column chromatography (PE/EA = 8:1). All the fractions (PE/EA = 2:1, R _f = 0.35) containing the product were judged by TLC to be combined and concentrated to give 2-(4-(5-ethoxy-6-) as a pale yellow oil. (4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (4- (3- hydroxy-2,2-dimethylpropyl) -3- ( Trifluoromethyl)phenyl)acetamide (3 g, 4.21 mmol, 82.0% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ: 7.93 (d, J = 2.0 Hz, 2H), 7.71 (d , J = 8.4 Hz, 1H), 7.47-7.31 (m, 7H), 6.90 (d, J = 8.4 Hz, 2H), 5.35 (s, 2H), 4.17-4.10 (m, 2H), 3.82-3.74 ( m, 5H), 3.31-3.30 (m, 2H), 2.77 (s, 2H), 1.41 (t, J = 6.8 Hz, 3H), 0.82 (s, 6H); ES-LCMS m/z 635 (M- 120).

Step 4: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (4- (3- hydroxy -2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

Containing N- (4-(3-((t-butyldimethylmethyl)alkyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)-2- (4-(5-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (3 g, 3.97 mmol) and HCl ( 4M 1,4-two The mixture was stirred at 25 ° C for 2 h. The mixture was concentrated. The crude product was purified twice by preparative HPLC (MeCN/H ₂ O as eluting solvent, acidic conditions) to yield 2-(4-(5-ethoxy-6-s-oxyl-1,6-di) as a white solid. hydrogen pyridin-3-yl) -2-fluorophenyl) - N - (4- (3- hydroxy-2,2-dimethylpropyl) -3- (trifluoromethyl) phenyl) acetyl amine (1528.59 mg, 2.94 mmol, 73.9% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ: 7.94 (d, J = 2.0 Hz, 1H), 7.74 - 7.67 (m, 1H), 7.44 - 7.38 ( m, 2H), 7.37-7.27 (m, 3H), 7.22 (d, J = 2.0 Hz, 1H), 4.11 (q, J = 6.8 Hz, 2H), 3.78 (s, 2H), 3.32-3.30 (m) , 2H), 2.77 (s, 2H), 1.45 (t, J = 6.8 Hz, 3H), 0.82 (s, 6H); ES-LCMS m/z 521 (M+1).

Example 6: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -3-fluorophenyl) - N - (4- (3- hydroxy -2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

Step 1: (4-Bromo-3-fluorophenyl)methanol

At 20 ℃, (100mL) was added dropwise in THF MeOH containing 4-bromo-3-fluorobenzaldehyde (10g, 49.3mmol) and NaBH ₄ (3.73g, 99mmol) of (100mL). LCMS analysis indicated that after the starting material had disappeared, solvent was evaporated in vacuo. The residue was dissolved in DCM (200mL), washed with H ₂ O (60mL) and brine (60mL). The organic layer was dried over sodium sulfate, filtered and concentrated to yield methanol (9.8g, 47.7mmol, 97.0% yield) as a white solid of ^{(4-bromo-3-fluorophenyl): 1 H NMR (400MHz,} CD 3 OD) δ 7.54 (t, J = 7.8 Hz, 1H), 7.18 (d, J = 9.6 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H), 4.56 (s, 2H); ES-LCMS m/z 188.9 (M-17).

Step 2: 1-Bromo-4-(bromomethyl)-2-fluorobenzene

Containing (4-bromo-3-fluorophenyl) methanol (5g, 24.39mmol) of DCM (100mL) was added dropwise a solution of PBr ₃ (2.76mL, 29.3mmol). The resulting mixture was stirred at 20 °C. After LCMS analysis showed that the starting material had disappeared, the mixture was adjusted to pH = 8 using aqueous Na ₂ CO ₃ . The organic layer was dehydrated and concentrated to give a crude material, which was purified by column chromatography (PE/EA = 10/1) to yield 1-bromo-4-(bromomethyl)-2-fluorobenzene (4.2 g, 14.89 mmol, 61.1% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.57 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 7.2 Hz, 1H), 7.16 (d, J = 6.4 Hz, 1H), 4.53 (s, 2H); ES-LCMS m/z 186.9 (M-79).

Step 3: 2-(4-Bromo-3-fluorophenyl)acetonitrile

KCN (0.243 g, 3.73 mmol) was added to a solution of 1-bromo-4-(bromomethyl)-2-fluorobenzene (1 g, 3.. The resulting mixture was stirred at 60 °C. After 3 h, LCMS analysis showed the starting material had disappeared. The solvent was removed in vacuo. The residue was dissolved in EA (80mL), washed with the use of H ₂ O (30mL) and brine (30mL). The organic layer was dehydrated and concentrated to give a crude material, which was purified by silica gel column chromatography (PE/EA = 10/1) to yield 2-(4-bromo-3-fluorophenyl)acetonitrile as a white solid (0.78 g) , 2.96 mmol, 79.0% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.63 (t, J = 7.8 Hz, 1H), 7.24 (d, J = 9.2 Hz, 1H), 7.12 (d, J = 9.6 Hz, 1H), 3.92 (s, 2H); ES-LCMS m/z 214.0 (M+H).

Step 4: 2-(4-Bromo-3-fluorophenyl)acetic acid

H A mixture of 2- (4-bromo-3-fluorophenyl) acetonitrile (0.78g, 3.64mmol) of ₂ SO ₄ (5mL) and H ₂ O (5mL) was stirred at 100 ℃ 16h. After LCMS analysis showed that the starting material had disappeared, the mixture was dissolved in H ₂ O (20mL), extracted with EA (20mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give a white solid of 2- (4-bromo-3-fluorophenyl) acetic acid (0.7g, 2.046mmol, 56.1% ^{yield): 1 H NMR (400MHz,} CD 3 OD) δ 7.53 (t, J = 7.8 Hz, 1H), 7.16 (dd, J = 9.8, 1.9 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 3.61 (s, 2H).

Step 5: 2- (4-bromo-3-fluorophenyl) - N - (4- (3 - (( tert-butyl-dimethyl-Si-alkyl) oxy) -2,2-dimethylpropyl) -3-(trifluoromethyl)phenyl)acetamide

Take 2-(4-bromo-3-fluorophenyl)acetic acid (50 mg, 0.215 mmol), 4-(3-((t-butyldimethylmethyl)alkyl)oxy-2,2-dimethyl DCM of propyl)-3-(trifluoromethyl)aniline (78 mg, 0.215 mmol), DIEA (83 mg, 0.644 mmol), HOBt (49.3 mg, 0.322 mmol) and EDC hydrochloride (61.7 mg, 0.322 mmol) The (20 mL) solution was stirred at 20 ° C for 16 h. A mixture of H ₂ O (20mL) and brine (20mL) and washed. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (PE / EA = 3/ 1) yielded the 2- (4-bromo-3-fluorophenyl) - N - (4- (3 - (( tert-butyl-dimethyl-Silane Oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (80 mg, 0.132 mmol, 61.4% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.83 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 6.6 Hz, 1H), 7, 49 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.15 (dd, J = 9.7, 1.8 Hz, 1H), 7.01 (d, J = 6.8 Hz, 1H), 3.62 (s, 2H), 2, 70 (s, 2H), 2.07 (s, 2H) ), 0.86 (s, 9H), 0.76-0.69 (m, 6H), 0.05-0.02 (m, 6H); ES-LCMS m/z 576.0 (M+H).

Step 6: N- (4-(3-((t-butyldimethylmethyl)alkyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)-2 -(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-3-fluorophenyl)acetamide

A mixture of 2- (4-bromo-3-fluorophenyl) - N - (4- (3 - (( tert-butyl-dimethyl-Si-alkyl) oxy) -2,2-dimethylpropyl) - 3-(Trifluoromethyl)phenyl)acetamide (80 mg, 0.139 mmol), 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (53.5 mg, 0.139 mmol), Cs ₂ CO ₃ (90 mg, 0.278 mmol), PdCl ₂ (dppf) ) (10.15mg, 0.014mmol) of 1,4-two Dioxane (9mL) and H ₂ O (3mL) was stirred for 15min at 110 ℃. LCMS analysis indicated that after the starting material had disappeared, solvent was evaporated in vacuo. The residue was dissolved in EA (60mL), washed with the use of H ₂ O (20mL) and brine (20mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (PE/EA = 2/1) to yield N- (4-(3-((t-butyl dimethyl decyl)))) --3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-3- Fluorophenyl)acetamide (100 mg, 0.111 mmol, 80.0% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.84 (d, J = 2.0 Hz, 1H), 7.77 (s, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.34-7.30 (m, 5H), 7.17-7.15 (m, 2H), 6.83 (d, J = 8.8 Hz, 2H), 5.27 (s, 2H), 4.04 3.99 (m, 4H), 3.70 (s, 3H), 3.66 (s, 2H), 3.24 (s, 2H), 2.69 (s, 2H), 1.31 (t, J = 7.0 Hz, 3H), 0.86 (s) , 9H), 0.73 (s, 6H), 0.00 (s, 6H); ES-LCMS m/z 755.2 (M+H).

Step 7: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -3-fluorophenyl) - N - (4- (3- hydroxy -2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

Containing N- (4-(3-((t-butyldimethylmethyl)alkyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)-2- (4-(5-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-3-fluorophenyl)acetamide (100 mg, 0.132 mmol) HCl ( The MeOH, 5 mL, 20.00 mmol) solution was stirred at 20 °C. LCMS analysis indicated that after the starting material had disappeared, solvent was evaporated in vacuo. The crude product was purified by preparative hp~~~~~~~~~~~~~~~~~~~~~^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ N- (4-(3-Hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (37.98 mg, 0.073 mmol, 55.1% yield): ¹ H NMR (400MHz, CD ₃ OD) 7.94 (d, J = 2.2 Hz, 1H), 7.70 (dd, J = 2.0, 8.4 Hz, 1H), 7.51-7.45 (m, 1H), 7.45-7.37 (m, 3H) ), 7.28-7.21 (m, 2H), 4.15 (m, 2H), 3.75 (s, 2H), 3.29 (broad s, 2H), 2.77 (s, 2H), 1.46 (t, J = 6.9 Hz, 3H) ), 0.82 (s, 6H); ES-LCMS m/z 521.2 (M+H).

Example 7: N- (4-Cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-o-oxy-1,6-dihydropyridine-3 -yl)-3-fluorophenyl)acetamide

Step 1: 2-(4-Bromo-3-fluorophenyl)acetate

To a solution of 2-(4-bromo-3-fluorophenyl)acetic acid (500 mg, 2.146 mmol) in MeOH (10 mL, 247 mmol) The resulting mixture was stirred at 60 °C. After 3 h, LCMS analysis showed the starting material had disappeared and solvent was evaporated in vacuo. The residue was dissolved in DCM (60mL), washed with NaHCO ₃ (20mL) and brine (20mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give a yellow oil of 2- (4-bromo-3-fluorophenyl) acetic acid methyl ester (500mg, 1.774mmol, 83.0% yield): ¹ H NMR ( 400MHz, CD ₃ OD) δ 7.53 (t, J = 8.0 Hz, 1H), 7.15 (dd, J = 9.8, 1.7 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 3.75-3.61 (m) , 5H); ES-LCMS m/z 248.9 (M+H).

Step 2: 2-(3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid methyl ester

Take 2-(4-bromo-3-fluorophenyl)acetic acid methyl ester (0.5g, 2.024mmol), 4,4,4',4',5,5,5',5'-octamethyl -2,2'-linked (1,3,2-dioxaborolane) (0.617 g, 2.429 mmol), PdCl ₂ (dppf) (0.148 g, 0.202 mmol) and KOAc (0.397 g, 4.05 mmol) 1,4-two The alkane (5 mL) solution was stirred at 80 ° C for 16 h. LCMS analysis indicated that after the starting material had disappeared, solvent was evaporated in vacuo. The residue was dissolved in EA (60 mL) and filtered. The filtrate using H ₂ O (20mL) and brine (20mL) and washed. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EtOAc/EtOAc/EtOAc) 2-Dioxaborolan-2-yl)phenyl)acetic acid methyl ester (440 mg, 1.294 mmol, 63.9% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.62 (t, J = 7.2 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 10.4 Hz, 1H), 3.67 (s, 5H), 1.33 (s, 12H); ES-LCMS m/z 295.1 (M+H).

Step 3: 2-(3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide

Taking methyl 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate ( 0.1 g, 0.340 mmol) of a solution of ammonia (MeOH, 10 mL, 160 mmol). LCMS analysis indicated that after the starting material had disappeared, solvent was removed in vacuo to yield 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan) -2-yl)phenyl)acetamidine (100 mg, 0.286 mmol, 84.0% yield): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.56 (t, J = 7.2 Hz, 1H), 7.14-6.98 (m, 2H), 3.59 (s, 2H), 1.26 (s, 12H); ES-LCMS m/z 280.1 (M+H).

Step 4: 2-(4-(6-(Benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)acetamide

2-(3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (100 mg) , 0.358 mmol), 2-(benzyloxy)-4-ethoxy-5-iodopyridine (127 mg, 0.358 mmol), PdCl ₂ (dppf) (26.2 mg, 0.036 mmol) and Cs ₂ CO ₃ (233 mg) , 0.717mmol) of 1,4-two Dioxane (6mL) and H ₂ O (2mL) was stirred for 15min at 110 ℃. LCMS analysis indicated that after the starting material had disappeared, solvent was evaporated in vacuo. The residue was dissolved in EA (40mL), washed with the use of H ₂ O (20mL) and brine (20mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (PE/EA = 1/1) to yield 2-(4-(6-(phenylmethyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl Acetamine (20 mg, 0.358 mmol, 14.8% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.87 (s, 1H), 7.56-7.43 (m, 2H), 7.43-7.22 (m, 4H) ), 7.21 - 7.11 (m, 2H), 6.50 (s, 1H), 5.38 (s, 2H), 4.13 (m, 2H), 3.58 (s, 2H), 1.32 (t, J = 6.8 Hz, 3H) ;ES-LCMS m/z 381.1 (M+H).

Step 5: 2- (4- (6- (benzyl oxy) -4-ethoxy-pyridin-3-yl) -3-fluorophenyl) - N - (4- cyano-3- (trifluoromethyl Methyl)phenyl)acetamide

2-(4-(6-(Benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)acetamide (20 mg, 0.053 mmol), 4-bromo-2 -(trifluoromethyl)benzonitrile (13.14 mg, 0.053 mmol), Pd ₂ (dba) ₃ (4.81 mg, 5.26 μmol), Xantphos (3.04 mg, 5.26 μmol) and Cs ₂ CO ₃ (34.3 mg, 0.105) Methyl) 1,4-two The alkane (2 mL) solution was stirred at 120 ° C for 1 h. LCMS analysis indicated that after the starting material had disappeared, solvent was evaporated in vacuo. The residue was dissolved in EtOAc (20 mL)EtOAcEtOAc The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (PE/EA=2/1) to yield 2-(4-(6-(phenylmethyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl - N- (4-Cyano-3-(trifluoromethyl)phenyl)acetamide (12 mg, 0.015 mmol, 28.5% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.25 (s , 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.84 (s, 1H), 7.59-7.48 (m, 1H), 7.43 - 7.28 (m, 5H), 7.23-7.15 (m, 2H), 6.46 (s, 1H), 5.34 (s, 2H), 4.09 (m, 2H), 3.73 (s, 3H), 1.28 (t, J = 6.4 Hz, 3H) ); ES-LCMS m/z 550.1 (M+H).

Step 6: N- (4-Cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-o-oxy-1,6-dihydropyridine-3) -yl)-3-fluorophenyl)acetamide

A mixture of 2- (4- (6- (benzyl oxy) -4-ethoxy-pyridin-3-yl) -3-fluorophenyl) - N - (4- cyano-3- (trifluoromethyl yl) phenyl) acetyl amine (12mg, 0.022mmol) and Pd / C (2.324mg, 0.022mmol) of MeOH (10mL) and H solution was stirred 20 ℃ gas mask ₂ 16h. After LCMS analysis indicated that the starting material had disappeared, the mixture was filtered. The filtrate was concentrated to give a crude material which was purified by preparative HPLC to give N- (4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6) -Sideoxy-1,6-dihydropyridin-3-yl)-3-fluorophenyl)acetamide (3.63 mg, 7.90 μmol, 36.2% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.23(s,1H),8.02-7.95(m,1H),7.94-7.88(m,1H),7.59(s,1H),7.35-7.29(m,1H),7.25-7.15(m,2H) , 6.23 (s, 1H), 4.16 (m, 2H), 3.80 (s, 2H), 1.32 (t, J = 7.0 Hz, 3H); ES-LCMS m/z 460.1 (M+H).

Example 8: 2- (2,6-difluorophenyl 4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)) - N - (4- ( 2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamide

Step 1: (4-Bromo-2,6-difluorophenyl)methanol

At room temperature, (5g, 21.10mmol) of THF (100mL) was added dropwise BH 2,6-difluorobenzoic acid in a solution of _{4-bromo-3 ˙DMS (20.03mL, 211mmol).} The resulting mixture was stirred at 60 ° C for 16 h. After LCMS analysis showed that the starting material had disappeared, the mixture was quenched with MeOH. The solvent was removed in vacuo to give (4-bromo-2,6-difluorophenyl)methanol (4.5 g, 20.02 mmol, 95.2% yield), which was used in the next step: ES-LCMS m/z 222.1 (M + 1).

Step 2: 5-Bromo-2-(bromomethyl)-1,3-difluorobenzene

Tribromophosphine (2.91 g, 10.76 mmol) was added to a solution of (4-bromo-2,6-difluorophenyl)methanol (2 g, 8. The resulting mixture was stirred at room temperature. After LCMS analysis showed that the starting material had disappeared, the mixture was washed with NaHCO ₃ (40 mL) and brine (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (PE/EA=5/1) to yield 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (1.6 g, 5.48 mmol, 61.2% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.12 (d, J = 6.8 Hz, 2H), 4.47 (s, 2H).

Step 3: 2-(4-Bromo-2,6-difluorophenyl)acetonitrile

KCN (0.401 g, 6.16 mmol) was added to a solution of 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (1.6 g, 5.60 mmol). The resulting mixture was stirred at 25 ° C for 16 h. The mixture was dissolved in H ₂ O (50mL), using EA (50mL) and extracted. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by EtOAc (EtOAc/EtOAc (EtOAc) % yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.39-7.36 (m, 2H), 3.89 (s, 2H).

Step 4: 2-(4-Bromo-2,6-difluorophenyl)acetic acid

A solution of H ₂ SO ₄ (3 mL, 56.3 mmol) and H ₂ O (3 mL, 167 mmol) containing 2-(4-bromo-2,6-difluorophenyl)acetonitrile (0.5 g, 2.155 mmol) at 60 ° C Stir under 16h. After LCMS analysis showed that the starting material had disappeared, the mixture was dissolved in H ₂ O (20mL), extracted with EA (2 x 30mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (PE/EA = 3/1 to 1/1) to yield 2-(4-bromo-2,6-difluorophenyl)acetic acid (0.3 g, 0.718 mmol, 33.3% yield: ¹ H NMR (400 MHz, CD ₃ OD) δ 7.13-7.05 (m, 2H), 3.71 (s, 2H).

Step 5: N- (4-(2-(Benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2,6-difluorophenyl) Acetamine

To a solution of 2-(4-bromo-2,6-difluorophenyl)acetic acid (0.3 g, 1.195 mmol) in EtOAc (5 mL, 1. The resulting mixture was stirred at 60 °C. After 2 h, LCMS analysis showed that the title material had disappeared, and solvent was evaporated from vacuo to yield 2-(4-bromo-2,6-difluorophenyl)ethylamine chloride (0.35 g, 0.832 mmol, 69.6% yield). Containing 4- (2- (phenylmethyl) ethoxy) -3- (trifluoromethyl) aniline (0.347g, 1.113mmol) and Et ₃ N (0.225g, 2.227mmol) of DCM (30mL) 2-(4-Bromo-2,6-difluorophenyl)acetamidine chloride (0.3 g, 1.113 mmol) was added to the solution. The resulting mixture was stirred at 25 °C. After LCMS analysis showed that the starting material had disappeared, a mixture of H ₂ O (20mL) and washed with brine (20mL). The organic layer was dried over sodium sulfate, filtered, concentrated and purified by preparative TLC (PE/EA=3/1) to give N- (4-(2-(phenylmethyloxy)ethoxy)-3- Trifluoromethyl)phenyl)-2-(4-bromo-2,6-difluorophenyl)acetamide (110 mg, 0.196 mmol, 17.6% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.81 (d, J = 2.8 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.32-7.25 (m, 7H), 7.15 (d, J = 8.8 Hz, 1H), 4.61 (s, 2H), 4.23 (t, J = 4.6 Hz, 2H), 3.84 (t, J = 4.6 Hz, 2H), 3.77 (s, 2H); ES-LCMS m/z 546.0 (M+H).

Step 6: N- (4-(2-(Benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-(( 4-methoxybenzyloxy)pyridin-3-yl)-2,6-difluorophenyl)acetamide

3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane) Pentane-2-yl)pyridine (78 mg, 0.202 mmol), N- (4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4) -Bromo-2,6-difluorophenyl)acetamide (110 mg, 0.202 mmol), PdCl ₂ (dppf)-DCM adduct (16.50 mg, 0.020 mmol) and Cs ₂ CO ₃ (132 mg, 0.404 mmol) 1,4-two Dioxane (6mL) and H ₂ O (2mL) was stirred for 15min at 110 ℃. LCMS analysis indicated that after the starting material had disappeared, solvent was evaporated in vacuo. The residue was dissolved in DCM (60mL), washed with the use of H ₂ O (20mL) and brine (20mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (DCM / MeOH = 10/1) to afford N - (4-(2-(phenylmethyloxy)ethoxy)-3-(trifluoromethyl)phenyl) -(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2,6-difluorophenyl)acetamide (70 mg, 0.071 mmol) , 35.1% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.97 (d, J = 2.0 Hz, 1H), 7.84 (s, 1H), 7.71 (d, J = 11.2 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 8.6 Hz, 2H), 7.37-7.13 (m, 8H), 6.90 (d, J = 8.6 Hz, 2H), 5.39-5.34 (m, 2H), 4.61 (s, 2H), 4.27-4.20 (m, 2H), 4.18-4.10 (m, 2H), 3.86-3.82 (m, 2H), 3.78 (s, 3H), 1.42 (t, J = 6.9 Hz, 3H), 1.19 (s, 2H); ES-LCMS m/z 723.2 (M+H).

Step 7: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2,6-difluorophenyl) - N - (4- ( 2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamide

Take N- (4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-(4) -Methoxybenzyl)oxy)pyridin-3-yl)-2,6-difluorophenyl)acetamide (70 mg, 0.097 mmol) and Pd/C (10.31 mg, 0.097 mmol) MeOH (10 mL) The solution was stirred under H ₂ atmosphere for 16 h. After LCMS analysis indicated that the starting material had disappeared, the mixture was filtered. The filtrate was concentrated to give a crude material which was purified by preparative HPLC to afford 2-(4-(5-ethoxy-6-s-oxyl-1,6-dihydropyridin-3-yl)-2 as a white solid. 6-difluorophenyl) - N - (4- (2- hydroxyethoxy) -3- (trifluoromethyl) phenyl) acetyl amine (7mg, 0.014mmol, 14.0% yield): ¹ H NMR (400MHz, CD ₃ OD) δ 7.83 (d, J = 2.4 Hz, 1H), 7.71 (d, J = 6.8 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.24 (dd, J =3.0, 5.4 Hz, 3H), 7.16 (d, J = 9.0 Hz, 1H), 4.07-4.20 (m, 4H), 3.87 (t, J = 5.0 Hz, 2H), 3.81 (s, 2H), 1.46 (t, J = 7.06 Hz, 3H); ES-LCMS m/z 513.1 (M+H).

Example 9: N- (4-Cyano-3-(trifluoro-methyl)phenyl)-2-(4-(5-ethoxy-6-yloxy-1,6-dihydro-pyridine) -3-yl)-2-fluorophenyl)acetamide

Step 1: 2-(4-Bromo-2-fluorophenyl)acetamide

To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (0.1 g, 0.429 mmol) in EtOAc (5 mL,EtOAc. The resulting mixture was stirred at 60 °C. After 2 h, the TLC assay (PE/EA = 1/1) showed that the starting material had disappeared. The solvent was removed in vacuo to give 2-(4-bromo-2-fluorophenyl)ethylamine chloride (110 mg, 0.416 mmol, 97% yield). A solution of 2-(4-bromo-2-fluorophenyl)acetamidine chloride (110 mg, 0.437 mmol) in THF (5 mL) The resulting mixture was stirred at 0 °C. LCMS analysis indicated that after the starting material had disappeared, solvent was evaporated in vacuo. The residue was dissolved in EtOAc (50 mL)EtOAcEtOAc The organic layer was dried and concentrated to give a white solid of 2- (4-bromo-2-fluorophenyl) acetyl amine (100mg, 0.280mmol, 63.9% yield), which was used without further purification the next step: ¹ H NMR (400MHz, CD ₃ OD) δ 7.32-7.30 (m, 2H), 7.24 (t, J = 8.2 Hz, 1H), 3.54 (s, 2H); ES-LCMS m/z 232.0 (M+H) .

Step 2: 2-(4-(5-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide

3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane) Pentane-2-yl)pyridine (133 mg, 0.345 mmol), 2-(4-bromo-2-fluorophenyl)acetamide (80 mg, 0.345 mmol), Cs ₂ CO ₃ (225 mg, 0.690 mmol) and PdCl ₂ (dppf) (25.2mg, 0.034mmol) of 1,4-two Dioxane (9mL) and H ₂ O (3mL) was stirred for 15min at 110 ℃. After LCMS analysis showed that the starting material had disappeared, the mixture was dissolved in H ₂ O (20mL), extracted with EA (50mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative EtOAc (EtOAc/EtOAc (EtOAc/EtOAc) 3-yl)-2-fluorophenyl)acetamide (90 mg, 0.219 mmol, 63.6% yield): ¹ H NMR (400 MHz, CD ₃ OD) 7.93 (d, J = 2.0 Hz, 1H), 7.43 7.34 (m, 6H), 6.91-6.89 (m, 2H), 5.35 (s, 2H), 4.16-4.11 (m, 2H), 3.78 (s, 3H), 1.41 (t, J = 7.0 Hz, 3H) ;ES-LCMS m/z 291.1 (M-120).

Step 3: N- (4-Cyano-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)) Pyridin-3-yl)-2-fluorophenyl)acetamide

Take 2-(4-(5-ethoxybenzyl-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (10 mg, 0.024 mmol) , 4-bromo-2-(trifluoromethyl)benzonitrile (6.09 mg, 0.024 mmol), Pd ₂ (dba) ₃ (2.231 mg, 2.436 μmol), Xamtphos (1.410 mg, 2.436 μmol) and Cs ₂ 1,4-two of CO ₃ (15.88 mg, 0.049 mmol) The alkane (1 mL) solution was stirred at 120 ° C for 1 h. LCMS analysis indicated that after the starting material had disappeared, solvent was evaporated in vacuo. The residue was dissolved in EtOAc (20 mL)EtOAcEtOAc The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (PE / EA = 1/ 1), was a white solid of N - (4- cyano-3- (trifluoromethyl) phenyl) -2- (4- (5-acetate Oxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (15 mg, 0.013 mmol, 51.4% yield): ¹ H NMR ( 400MHz, CD ₃ OD) δ 8.23(s,1H), 7.98(m,1H), 7.94-7.90(m,2H),7.44-7.37(m,6H),6.90(d, J =8.4Hz, 2H) , 5.32 (s, 2H), 4.16-4.11 (m, 2H), 2.85 (s, 2H), 3.77 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H); ES-LCMS m/z 460.1 (M-120).

Step 4: N- (4-Cyano-3-(trifluoro-methyl)phenyl)-2-(4-(5-ethoxy-6-yloxy-1,6-dihydro-pyridine) -3-yl)-2-fluorophenyl)acetamide

Containing N- (4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl))oxy)pyridine A solution of -3-yl)-2-fluorophenyl)acetamide (15 mg, 0.026 mmol) in EtOAc (MeOH (EtOAc) LCMS analysis indicated that after the starting material had disappeared, solvent was evaporated in vacuo. The crude product was purified by preparative HPLC to give N- (4-cyano-3-(trifluoro-methyl)phenyl)-2-(4-(5-ethoxy-6-yloxy) -1,6-Dihydropyridin-3-yl)-2-fluorophenyl)acetamide (3 mg, 6.39 μmol, 24.7% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.23 (s, 1H), 7.99 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.41 (m, 1H), 7.37-7.34 (m, 3H), 7.29 (d, J = 2.0 Hz, 1H), 4.17-4.11 (m, 2H), 3.84 (s, 2H), 1.46 (t, J = 6.8 Hz, 3H); ES-LCMS m/z 460.1 (M+H).

Example 10: N- (6-(2-(Dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(4-ethoxy)- 6-Sideoxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidamine dihydrochloride

Step 1: 5-Nitro-3-(trifluoromethyl)pyridin-2-ol

(Trifluoromethyl) pyridin-2-ol (5g, 30.7mmol) ice cold solution of H ₂ SO ₄ (30mL, _563mmol) was added dropwise nitric acid (1.507mL, 33.7mmol) containing 3- After 30 minutes, the ice bath was left and the reaction mixture was stirred at 25 ° C for 16 h. The reaction mixture was warmed to 60 ° C over 5 hours, cooled, and added to 150 g of ice. The resulting precipitate was collected by filtration, rinsed using H ₂ O, and air-dried to produce a first crop. The mother liquor was evaporated to less than 100 mL to give another batch of product which was cooled on an ice bath and adjusted to pH 8 with NaOH. The mixture was extracted with EA (100 mL). The organic layer was dehydrated and concentrated to give a product which was combined with the first crop to give 5-nitro-3-(trifluoromethyl)pyridin-2-ol (5 g, 24.03 mmol, 78.0% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.85 (d, J = 3.2 Hz, 1H), 8.58 (d, J = 2.8 Hz, 1H).

Step 2: 2-Chloro-5-nitro-3-(trifluoromethyl)pyridine

Containing 5-nitro-3- (trifluoromethyl) SOCl2-2-ol (1g, 4.81mmol) of ₂ (10mL, 137mmol) was added DMF (0.372mL, 4.81mmol). The resulting mixture was stirred at 80 ° C for 16 h. TLC analysis indicated that after the starting material had disappeared, the solvent was removed in vacuo. The residue was dissolved in DCM (60mL), washed with aqueous NaHCO ₃ (20mL) and brine (20mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (EtOAc/EtOAc (EtOAc/EtOAc) Rate: ¹ H NMR (400 MHz, CD ₃ OD) δ 9.42 (d, J = 2.8 Hz, 1H), 8.91 (d, J = 2.4 Hz, 1H).

Step 3: N , N -Dimethyl-2-((5-nitro-3-(trifluoromethyl)pyridin-2-yl)oxy)ethylamine

2-Chloro-5-nitro-3-(trifluoromethyl)pyridine (0.5, 2.207 mmol) and 2-(dimethylamino)ethanol (0.393 g, 4.41 mmol) at 0 °C NaH (0.177 g, 4.41 mmol) was added to a solution of THF (10 mL). The resulting mixture was stirred at room temperature. After 5 hours, TLC analysis showed the starting material had disappeared. The solvent was removed in vacuo. The residue was dissolved in DCM (60mL), washed with the use of H ₂ O (20mL) and brine (20mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography (DCM /MeOH = 20/1) to yield N , N -dimethyl-2-((5-nitro-3-(trifluoromethyl)) as a white solid. Pyridin-2-yl)oxy)ethylamine (0.5 g, 1.718 mmol, 78.0% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 9.25 (d, J = 2.4 Hz, 1H), 8.74 (d, J = 2.4 Hz, 1H), 4.73 (t, J = 5.4 Hz, 2H), 2.88 (t, J = 5.4 Hz, 2H), 2.37 (s, 6H); ES-LCMS m/z 280.0 (M+H) ).

Step 4: 6-(2-(Dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-amine

Take N , N -dimethyl-2-((5-nitro-3-(trifluoromethyl)pyridin-2-yl)oxy)ethylamine (500 mg, 1.791 mmol) and Pd/C (191 mg, A solution of 1.791 mmol) in MeOH (30 mL) was stirred at 20 ° C with hydrogen. After TLC analysis (DCM / MeOH = 20/1) showed that the starting material had disappeared, the mixture was filtered. The filtrate was concentrated to give 6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-amine (360 mg, 1.44 mmol, 81.1% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.77 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 3.2 Hz, 1H), 4.43 (t, J = 5.6 Hz, 2H), 2.78 (t) , J = 6.4 Hz, 2H), 2.35 (s, 6H); ES-LCMS m/z 250.1 (M+H).

Step 5: 2- (4-bromo-2-fluorophenyl) - N - (6- (2- ( dimethylamino) ethoxy) -5- (trifluoromethyl) pyridin-3-yl Ethylamine

In 2-(4-bromo-2-fluorophenyl)acetic acid (100 mg, 0.429 mmol), 6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridine- DIEA (0.225 mL, 1.287 mmol) was added to a solution of EtOAc (EtOAc). The resulting mixture was stirred at 20 ° C for 16 h. A mixture of H ₂ O (20mL) and brine (20mL) and washed. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (DCM / MeOH = 10/ 1) yielded the brown oil of 2- (4-bromo-2-fluorophenyl) - N - (6- (2- ( dimethylamine Ethyloxy)-5-(trifluoromethyl)pyridin-3-yl)acetamide (130 mg, 0.273 mmol, 63.7% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.51 (d , J = 2.0 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 7.38-7.26 (m, 4H), 4.62 (t, J = 5.4 Hz, 2H), 3.75 (s, 2H), 3.08 (t, J = 5.2 Hz, 2H), 2.56 (s, 6H); ES-LCMS m/z 464.0 (M+H).

Step 6: N- (6-(2-(Dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-2-(2-fluoro-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide

A mixture of 2- (4-bromo-2-fluorophenyl) - N - (6- (2- ( dimethylamino) ethoxy) -5- (trifluoromethyl) pyridin-3-yl) Acetamide (0.1g, 0.215mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxo Boracyclopentane) (0.066g, 0.258mmol), PdCl ₂ (dppf) (0.016g, 0.022mmol) and KOH of 0.0Ac (0.042g, 0.431mmol) The alkane (5 mL) solution was stirred at 80 ° C for 16 h. LCMS analysis indicated that after the starting material had disappeared, solvent was evaporated in vacuo. The residue was purified by preparative TLC (DCM / MeOH = 20/1) to afford N- (6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridine-3- 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamidamine 42mg, 0.076mmol, 35.4% ^{yield): 1 H NMR (400MHz,} CD 3 OD) δ 8.56 (s, 1H), 8.30 (s, 1H), 7.51 (d, J = 7.6Hz, 1H), 7.43- 7.30 (m, 2H), 4.75-4.68 (m, 2H), 3.80 (s, 2H), 3.41 (s, 2H), 2.82 (s, 6H), 1.33 (s, 12H); ES-LCMS m/z 512.2 (M+H).

Step 7: 2- (4- (6- (benzyl oxy) -4-ethoxy-pyridin-3-yl) -2-fluorophenyl) - N - (6- (2- ( dimethylamine Ethyloxy)-5-(trifluoromethyl)pyridin-3-yl)acetamide

Containing N- (6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-2-(2-fluoro-4-(4,4) ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamidamine (30 mg, 0.059 mmol), 2-(benzyloxy)-4 - ethoxy-5-iodopyridine (20.84 mg, 0.059 mmol), PdCl ₂ (dppf) (42.9 mg, 0.059 mmol) and Cs ₂ CO ₃ (19.12 mg, 0.059 mmol) 1,4-two Dioxane (3mL) and H ₂ O (1mL) was stirred for 15min at 110 ℃. LCMS analysis indicated that after the starting material had disappeared, solvent was evaporated in vacuo. The residue was dissolved in EA (30mL), washed with the use of H ₂ O (10mL) and brine (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (DCM / MeOH = 10/1) to give 2-(4-(6-(phenylmethyloxy)-4-ethoxypyridin-3-yl)-2-fluorophenyl ) - N - (6- (2- ( dimethylamino) ethoxy) -5- (trifluoromethyl) pyridin-3-yl) acetyl amine (5mg, 6.97μmol, 11.9% yield) : ¹ H NMR (400 MHz, CD ₃ OD) δ 8.56 (s, 1H), 8.33 (d, J = 2.0 Hz, 1H), 7.99 (s, 1H), 7.48-7.30 (m, 8H), 6. , 1H), 5.38 (s, 2H), 4.64 (t, J = 5.2 Hz, 2H), 4.16 (m, 2H), 3.84 (s, 2H), 3.03 (t, J = 5.2 Hz, 2H), 2.53 (s, 6H), 1.40 (t, J = 7.0 Hz, 3H); ES-LCMS m/z 613.1 (M+H).

Step 8: N- (6-(2-(Dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(4-ethoxy)- 6-Sideoxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidamine dihydrochloride

A mixture of 2- (4- (6- (benzyl oxy) -4-ethoxy-pyridin-3-yl) -2-fluorophenyl) - N - (6- (2- ( dimethylamino a solution of ethoxy)-5-(trifluoromethyl)pyridin-3-yl)acetamide (5 mg, 8.16 μmol) and Pd/C (0.869 mg, 8.16 μmol) in MeOH (10 mL) at 20 ° C The mixture was stirred under hydrogen atmosphere (0.016 mg, 8.16 μmol) for 16 h. LCMS analysis indicated the mixture was filtered after the starting material had been consumed. The filtrate was concentrated to give a crude product which was purified by preparative HPLC to give a colorless oil of N - (6- (2- (dimethylamino) ethoxy) -5- (trifluoromethyl) pyridin-3 -yl)-2-(4-(4-ethoxy-6-oxooxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidamine dihydrochloride (1 mg , 1.680μmol, 20.6% yield): ¹ H NMR (400MHz, CD ₃ OD) δ 8.63 (s, 1H), 8.37 (s, 1H), 7.62 (d, J = 6.4 Hz, 1H), 7.46-7.42 (m, 1H), 7.31-7.28 (m, 2H), 6.21 (d, J = 11.8 Hz, 1H), 4.23-4.18 (m, 2H), 3.86 (s, 2H), 3.69-3.67 (m, 2H) ), 3.33 (m, 2H), 3.04 (s, 6H), 1.42 (t, J = 7.0 Hz, 3H); ES-LCMS m/z 523.2 (M+H).

Example 11: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (4- methyl Base-1 H -imidazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide hydrochloride

A suspension containing 3-(4-methyl-1 H -imidazol-1-yl)-5-(trifluoromethyl)aniline (6.63 mg, 0.027 mmol) in DMF (5 mL) -(5-Ethoxy-6-o-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid (8 mg, 0.027 mmol) in DMF (5 mL). Was added HOBt (6.31mg, 0.041mmol), EDC (7,90mg, 0.041mmol) and _{Et 3 N (0.011mL, 0.082mmol)} , the mixture was stirred at 50 ℃ 12h. The solution was then concentrated, and dissolved points between EA and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/H ₂ O as eluting solvent, acidic conditions) to yield 2-(4-(5-ethoxy-6-s-oxyl-1,6-dihydropyridine) as an off-white solid. 3-yl) -2-fluorophenyl) - N - (3- (4- methyl -1 H - imidazol-1-yl) -5- (trifluoromethyl) phenyl) acetyl amine hydrochloride Salt (1.60 mg, 2.90 μmol, 10.6% yield). TLC (DCM / MeOH = 10: 1, R f = 0.3): 1 H NMR (400MHz, CD3OD) δ: 9.41 (d, J = 1.54Hz, 1H), 8.37-8.45 (m, 1H), 7.96 (s , 1H), 7.73-7.88 (m, 2H), 7.18-7.52 (m, 5H), 4.14 (q, J = 7.06 Hz, 2H), 3.87 (s, 2H), 2.43 (s, 3H), 1.46 ( t, J = 6.95 Hz, 3H); ES-LCMS m/z 515.1 (M+H).

Example 12: N- (6-(2-Cyanopropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-side) Oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide hydrochloride

Step 1: 2-Methyl-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanenitrile

K ₂ CO ₃ (359 mg, 2.60 mmol) was added to a solution of 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetonitrile (200 mg, 0.8. MeI (3071 mg, 21.63 mmol) was added and the mixture was taken at 40 ° C for 10 h. The solution was then concentrated, and dissolved points between EA and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (PE / EA = 5: 1, R f = 0.5) yielded the pale yellow solid of 2-methyl-2- (5-nitro-3- (trifluoromethyl) pyridin - 2-yl)propanenitrile (129 mg, 0.498 mmol, 57.5% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ: 9.54 (d, J = 2.2 Hz, 1H), 8.65-9.07 (m, 1H), 1.92 (s, 6H); ES-LCMS m/z 260.1 (M+H).

Step 2: 2-(5-Amino-3-(trifluoromethyl)pyridin-2-yl)-2-methylpropanenitrile

Add tin(II) chloride dihydrate (449 mg, 1.991 mmol) to 2-methyl-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanenitrile (129 mg, 0.498 mmol) in EA (15 mL) solution. The mixture was at 60 ° C for 4 h. The solution was then adjusted to pH = 8-9 using 2N NaOH. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/H ₂ O as solvent eluting, basic conditions) to yield 2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)-2 as a white solid. Methylpropionitrile (46.48 mg, 0.203 mmol, 40.7% yield). TLC (PE/EA = 1:1, _Rf = 0.3): ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.04-8.17 (m, 1 H), 7.31 (d, J = 2.43 Hz, 1 H) , 5.97 (s, 2 H), 1.70 (s, 6 H); ES-LCMS m/z 230.1 (M+H).

Step 3: N- (6-(2-Cyanopropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6- side) Oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide hydrochloride

Add a suspension of 2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)-2-methylpropanenitrile (13.91 mg, 0.061 mmol) in DMF (5 mL). (4-(5-Ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid (52 mg, EtOAc) Was added HOBt (13.94mg, 0.091mmol), EDC (17.45mg, 0.091mmol) and _{Et 3 N (0.025mL, 0.182mmol)} , the mixture at 50 deg.] C under 12h. The solution was then concentrated, and dissolved points between EA and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC The crude product (MeCN / H ₂ O as the eluent, acidic conditions) to give an off-white solid of N - (6- (2- cyanopropan-2-yl) -5- (trifluoromethyl) Pyridin-3-yl)-2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide hydrochloride (8.62 mg, 0.016 mmol, 26.4% yield). TLC (DCM / MeOH = 10:1, _Rf = 0.3): ¹ H NMR (400 MHz, CD ₃ OD) δ: 8.95 (d, J = 2.2 Hz, 1H), 8.56 (d, J = 2.4 Hz, 1H) ), 7.26-7.47 (m, 5H), 4.14 (q, J = 7.0 Hz, 2H), 3.81-3.90 (m, 2H), 1.77-1.91 (m, 6H), 1.47 (t, J = 6.9 Hz, 3H); ES-LCMS m/z 503.1 (M+H).

Example 13: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (4- (2- hydroxy Ethoxy)-3-(trifluoromethyl)phenyl)acetamide

Step 1: N- (4-(2-(Benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2-fluorophenyl)acetamide

A suspension of 4-(2-(benzylideneoxy)ethoxy)-3-(trifluoromethyl)aniline (668 mg, 2.146 mmol) in DCM (35 mL). 2-Fluorophenyl)acetic acid (500 mg, 2.146 mmol) in DCM (35 mL). Was added HOBt (493mg, 3.22mmol), EDC (617mg, 3.22mmol) and _{Et 3 N (0.897mL, 6.44mmol)} , the mixture was stirred at 26 ℃ 3h. The solution was then concentrated, and dissolved points between EA and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by column chromatography (PE/EA = 10/1). All the fractions containing the product (PE/EA = 5/1, R _f 0.6) were judged by TLC to be combined and concentrated to give N- (4-(2-(phenylmethyloxy)ethoxy) as a pale yellow solid. -3-(Trifluoromethyl)phenyl)-2-(4-bromo-2-fluorophenyl)acetamide (1 g, 1.900 mmol, 89.0% yield): ¹ H NMR (400 MHz, CD ₃ OD ) δ 7.83-7.82 (d, J = 2.8 Hz, 1H), 7.33 - 7.24 (m, 10H), 4.83 (s, 1H), 4.23-4.21 (m, 2H), 3.84 - 3.83 (m, 2H), 3.71-3.67 (m, 2H); ES-LCMS m/z 525.9 (M+H).

Step 2: N- (4-(2-(Benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-(( 4-methoxybenzyloxy)pyridin-3-yl)-2-fluorophenyl)acetamide

Taking N- (4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2-fluorophenyl)acetamide ( 800mg, 1.520mmol) of 1,4-two Add a suspension of alkane (3 mL) and H ₂ O (1 mL) to 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetra 1,4-dimethyl-1,3,2-dioxaborolan-2-yl)pyridine (586 mg, 1.520 mmol) Alkane (3 mL) in H ₂ O (1 mL) solution. PdCl ₂ (dppf) (111 mg, 0.152 mmol) and Cs ₂ CO ₃ (990 mg, 3.04 mmol) were added, and the mixture was stirred at 110 ° C for 30 min. The mixture was cooled to room temperature. The solution was then concentrated, and dissolved points between EA and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (PE / EA = 1/1 , R f = 0.5), a light yellow solid of N - (4- (2- (phenylmethyl) ethoxy) -3- (C Fluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamidine Amine (230 mg, 0.326 mmol, 21.5% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.95-7.94 (d, J = 2.0 Hz, 1H), 7.90-7.89. (d, J = 2.8 Hz, 1H), 7.45-7.38 (m, 6H), 7.37-7.25 (m, 6H), 6.92-6.90 (m, 2H), 5.36 (s, 2H), 4.61 (s, 2H), 4.25-4.24 (m, 2H), 4.23-4.11 (m, 2H), 3.85-3.83 (m, 2H), 3.79-3.77 (m, 2H), 1.45-1.41 (t, J = 4.8 Hz, 3H); ES-LCMS m/z 705.1 (M+H).

Step 3: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (4- (2- hydroxy Ethoxy)-3-(trifluoromethyl)phenyl)acetamide

Take N- (4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-(4) -Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamidamine (50 mg, 0.071 mmol) in MeOH (10 mL) was added to Pd/C (15.10 mg, 0.142) Methyl) in MeOH (10 mL). The mixture was hydrogenated at H _{2 for 2} h at 26 °C. The solution was then filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/H ₂ O as eluting solvent, basic conditions) to yield 2-(4-(5-ethoxy-6-s-oxyl-1,6-dihydro) as a white solid. pyridin-3-yl) -2-fluorophenyl) - N - (4- (2- hydroxyethoxy) -3- (trifluoromethyl) phenyl) acetyl amine (26.17mg, 0.053mmol, 74.6 %Yield). TLC (DCM / MeOH = 10/ 1, R f = 0.4): 1 H NMR (400MHz, CD 3 OD) δ 7.84-7.83 (m, 1H), 7.72-7.70 (d, J = 8.8Hz, 1H), 7.43-7.41(m,1H), 7.39-7.29(m,3H), 7.23-7.22(d, J =2.0Hz,1H), 7.17-7.15(d, J =9.2Hz,1H),4.14-4.11( m, 4H), 3.88-3.86 (m, 2H), 3.76 (s, 2H), 1.47-1.44 (t, J = 7.0 Hz, 3H); ES-LCMS m/z 495.0 (M+H).

Example 14: N- (6-(Cyanomethyl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-o-oxy-1, 6-Dihydropyridin-3-yl)-2-fluorophenyl)acetamide hydrochloride

Step 1: 2-(5-Amino-3-(trifluoromethyl)pyridin-2-yl)acetonitrile

Add a solution of tin(II) chloride dihydrate (58.6 mg, 0.260 mmol) in EA (60 mL) to 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetonitrile (30 mg, 0.130 mmol) in EA (60 mL). The mixture was allowed to stand at 50 ° C for 3 h. The solution was then concentrated, and dissolved points between EA and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting 2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)acetonitrile (16 mg, 0.080 mmol, 61.3% yield) was used for the next step without further purification. TLC (PE/EA = 1:1, R _f = 0.5): ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.19-8.27 (m, 1H), 7.22 (d, J = 2.5 Hz, 1H), 3.97 ( s, 2H); ES-LCMS m/z 202.0 (M+H).

Step 2: N- (6-(Cyanomethyl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-yloxy-1, 6-Dihydropyridin-3-yl)-2-fluorophenyl)acetamide hydrochloride

A suspension of 2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)acetonitrile (16.00 mg, 0.080 mmol) in DMF (5 mL) was added to 2-(4-(5-) A solution of ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid (46.33 mg, 0.080 mmol) in DMF (5 mL). Was added HOBt (18.27mg, 0.119mmol), EDC (22,87mg, 0.119mmol) and _{Et 3 N (0.033mL, 0.239mmol)} , the mixture at 50 deg.] C under 12h. The solution was then concentrated, and dissolved points between EA and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/H ₂ O eluting solvent, acidic conditions) to yield N- (6-(cyanomethyl)-5-(trifluoromethyl)pyridin-3-yl as a yellow solid. 2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide hydrochloride (0.96 mg, 1.879) Μmol, 2.4% yield). TLC (DCM / MeOH = 10:1, _Rf = 0.3): ¹ H NMR (400 MHz, CD ₃ OD) δ: 8.87-8.96 (m, 1 H), 8.56 (d, J = 2.21 Hz, 1 H) , 7.19-7.50 (m, 5 H), 4.08-4.18 (m, 2 H), 3.85 (s, 3 H), 3.58 (s, 2 H), 1.29-1.35 (m, 3 H); ES-LCMS m/z 475.0 (M+H).

Example 15: N- (6-(1-Cyanoethyl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-yloxy)- 1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide hydrochloride

Step 1: 2-(5-Nitro-3-(trifluoromethyl)pyridin-2-yl)propanenitrile

K ₂ CO ₃ (359 mg, 2.60 mmol) was added to a solution of 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetonitrile (200 mg, 0.8. MeI (3071 mg, 21.63 mmol) was added and the mixture was stirred at 40 ° C for 10 h. The solution was then concentrated, and dissolved points between EA and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative EtOAc (EtOAc/EtOAc (EtOAc/EtOAc) (73.6 mg, 0.300 mmol, 34.7% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ: 9.65 (d, J = 2.2 Hz, 1H), 9.54 (d, J = 2.2 Hz, 1H), 8.86 ( d, J = 2.2 Hz, 1H), 8.80 (d, J = 2.0 Hz, 1H), 4.47 (q, J = 7.1 Hz, 1H), 1.92 (s, 2H), 1.78 (d, J = 7.1 Hz, 3H); ES-LCMS m/z 246.0 (M+H).

Step 2: 2-(5-Amino-3-(trifluoromethyl)pyridin-2-yl)propanenitrile

Add tin(II) chloride dihydrate (135 mg, 0.600 mmol) to 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanenitrile (73.6 mg, 0.300 mmol) EA (15 mL) in solution. The mixture was allowed to stand at 50 ° C for 3 h. The solution was then concentrated, and dissolved points between EA and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting 2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)propanenitrile (55 mg, 0.256 mmol, 85.0% yield) was used for the next step without further purification. TLC (PE/EA = 5:1, R _f = 0.5): ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.25 (s, 1H), 7.17 (d, J = 2.2 Hz, 1H), 4.15 - 4.28 ( m, 1H), 1.66 (d, J = 7.1 Hz, 3H); ES-LCMS m/z 216.0 (M+H).

Step 3: N- (6-(1-Cyanoethyl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-yloxy)- 1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide hydrochloride

Add a suspension of 2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)propanenitrile (55.6 mg, 0.258 mmol) in DMF (10 mL) to 2-(4-(5) A solution of ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid (125.4 mg, 0.258 mmol) in DMF (10 mL). HATU (147 mg, 0.387 mmol) and DIEA (0.135 mL, 0.775 mmol) were added and the mixture was taken at 50 ° C for 12 h. The solution was then concentrated, and dissolved points between EA and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/H ₂ O eluting solvent, acidic conditions) to yield N- (6-(1-cyanoethyl)-5-(trifluoromethyl)pyridine-3 as an off-white solid. -yl)-2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidine hydrochloride (10.59 mg , 0.020 mmol, 7.8% yield). TLC (DCM / MeOH = 10:1, _Rf = 0.3): ¹ H NMR (400 MHz, CD ₃ OD) δ: 8.96 (s, 1H), 8.49 - 8.65 (m, 1H), 7.17-7.53 (m, 5H), 4.46 (q, J = 7.0 Hz, 1H), 4.07-4.20 (m, 2H), 3.86 (s, 2H), 1.67 (d, J = 7.1 Hz, 3H), 1.37-1.53 (m, 3H) ); ES-LCMS m/z 489.1 (M+H).

Example 16: N- (4-Chloro-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridine-3- 2-fluorophenyl)acetamide

A suspension of 4-chloro-3-(trifluoromethyl)aniline (20.14 mg, 0.103 mmol) in DMF (8 mL) was added to 2-(4-(5-ethoxy-6-s-oxy)- A solution of 1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid (30 mg, 0.103 mmol) in DMF (8 mL). Was added HOBt (23.66mg, 0.154mmol), EDC (29.6mg, 0.154mmol) and _{Et 3 N (0.043mL, 0.309mmol)} , the mixture was stirred at 50 deg.] C 8h. The solution was then concentrated, and dissolved points between EA and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN / H ₂ O as the eluent, acidic conditions), a white solid of N - (4- chloro-3- (trifluoromethyl) phenyl) -2- (4- ( 5-Ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide (11.39 mg, 0.024 mmol, 23.6% yield). TLC (DCM/MeOH = 10:1, _Rf = 0.6): ¹ H NMR (400 MHz, CD ₃ OD) δ: 8.10 (s, 1 H), 7.79 (d, J = 8.82 Hz, 1H), 7. d, J = 8.82 Hz, 1H), 7.37-7.44 (m, 1H), 7.26-7.37 (m, 3H), 7.23 (d, J = 1.98 Hz, 1H), 4.12 (q, J = 7.06 Hz, 2H) ), 3.80 (s, 2H), 1.46 (t, J = 6.95 Hz, 3H); ES-LCMS m/z 469.1 (M+H).

Example 17: N- (4-((Dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-yloxy)- 1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide hydrochloride

Step 1: N , N -Dimethyl-4-nitro-2-(trifluoromethyl)benzamide

4-nitro-2-(trifluoromethyl)benzoic acid (10 g, 42.5 mmol), dimethylamine (hydrochloride, 4.51 g, 55.3 mmol) and Et in a nitrogen atmosphere at 20 ° C A total amount of HATU (19.41 g, 51.0 mmol) was added in one portion of a solution of &lt;₃&gt;N (17.78 <RTIgt; The reaction mixture was stirred at 20 ° C for 2 h. The solution was then dissolved in divided between DCM and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting N , N -dimethyl-4-nitro-2-(trifluoromethyl)benzamide (10 g, 25.2 mmol, 59.2% yield) was used in the next step without further purification. TLC (PE/EA = 5:1, _Rf 0.6): ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.57 (d, J = 1.8 Hz, 1H), 8.46 (dd, J = 2.0, 8.4 Hz, 1H) , 7.58 (d, J = 8.4 Hz, 1H), 2.79 (s, 6H); ES-LCMS m/z 263.0 (M+H).

Step 2: 4-Amino- N , N -dimethyl-2-(trifluoromethyl)benzamide

Once in a solution of N , N -dimethyl-4-nitro-2-(trifluoromethyl)benzamide (10 g, 25.2 mmol) in MeOH (100 mL) with aq. A full amount of Pd/C (1 g, 9.40 mmol) was added. The reaction mixture was stirred with H ₂ atmosphere and 20 ° C for 12 h. The mixture was filtered, and the filtrate concentrated in vacuo to yield the desired product 4-amino - N, N - dimethyl-2- (trifluoromethyl) benzoyl amine (8.3g, 23.59mmol, 94.0% yield). TLC (DCM / MeOH = 10: 1, R f = 0.4): 1 H NMR (400MHz, CDCl 3) δ 7.07 (d, J = 8.2Hz, 1H), 6.90 (s, 1H), 6.79 (d, J = 8.2 Hz, 1H), 3.95 (br.s., 2H), 3.08 (s, 3H), 2.80 (s, 3H); ES-LCMS m/z 233.0 (M+H).

Step 3: 4-((Dimethylamino)methyl)-3-(trifluoromethyl)aniline

In a solution of 4-amino- N , N -dimethyl-2-(trifluoromethyl)benzamide (8.3 g, 23.59 mmol) in THF (100 mL), stirred at 20 ° C. BH ₃ ‧ DMS (11.20 mL, 118 mmol) was added dropwise. The reaction mixture was stirred at 80 ° C for 2 h. After adding MeOH to the solution, it was concentrated in vacuo to give crude material. The crude product was purified by flash column chromatography (DCM /MeOH = 30:1). All the fractions containing the product (DCM/MeOH = 10:1, R _f = 0.4) were determined by TLC to be combined and concentrated to give 4-((dimethylamino)methyl)-3 as a pale yellow oil. - (trifluoromethyl) aniline (4g, 18.33mmol, 78.0% ^{yield): 1 H NMR (400MHz,} CD 3 OD) 87.99 (d, J = 8.0Hz, 1H), 7.73 (s, 1H), 7.67 (d, 8.0 Hz, 1H), 4.57 (s, 2H), 2.96 (s, 6H); ES-LCMS m/z 219.2 (M+H).

Step 4: 2- (4-bromo-2-fluorophenyl) - N - (4 - ( ( dimethylamino) methyl) -3- (trifluoromethyl) phenyl) acetyl amine

4-((Dimethylamino)methyl)-3-(trifluoromethyl)aniline dihydrochloride (4 g, 13.74 mmol), 2-(4-) stirred under nitrogen at 20 ° C bromo-2-fluorophenyl) acetic acid (3.20g, 13.74mmol) and Et ₃ N (9.57mL, 68.7mmol) of DCM (100mL) was added in a total amount of EDC (2.63g, 13.74mmol) and HOBt (2.104g , 13.74mmol). The reaction mixture was stirred at 20 ° C for 2 h. The solution was then concentrated, and dissolved points between EA and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by column chromatography (PE/EA = 3:1). TLC taken by the determination of the product-containing fractions were all dissolved (PE / EA = 2: 1 , R f 0.6) were combined and concentrated to give a pale yellow solid of 2- (4-bromo-2-fluorophenyl) - N - (4 -((Dimethylamino)methyl)-3-(trifluoromethyl)phenyl)acetamide (5.5 g, 9.14 mmol, 66.5% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.79 (br.s., 2H), 7.70 (d, J = 5.02 Hz, 2H), 7.30 (br.s., 2H), 3.73 (s, 2H), 3.53 (s, 2H), 2.47 (s, 6H); ES-LCMS m/z 435.0 (M+H).

Step 5: N- (4-((Dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-(4- Methoxybenzyloxy)pyridin-3-yl)-2-fluorophenyl)acetamide

3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1, which is stirred under nitrogen at 20 ° C, 3,2-dioxaborolan-2-yl) pyridine (3.52g, 9.14mmol), 2- ( 4- bromo-2-fluorophenyl) - N - (4 - ( ( dimethylamine Methyl)-3-(trifluoromethyl)phenyl)acetamide (5.5 g, 9.14 mmol) and Cs ₂ CO ₃ (7.45 g, 22.85 mmol) 1,4-di A full amount of PdCl ₂ (dppf) (0.334 g, 0.457 mmol) was added in one portion of a solution of aq. (30 mL) and H ₂ O (10.00 mL). The reaction flask was heated at 110 ° C for 3 h. The solution was then concentrated, and dissolved points between EA and H ₂ O. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by column chromatography (PE/EA = 1:1). All the fractions containing the product (PE/EA = 1:1, R _f 0.3) were judged by TLC to be combined and concentrated to give N- (4-((dimethylamino)methyl)-3- as a white solid. (trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl) Acetamide (5.8 g, 7.30 mmol, 80.0% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.80-7.98 (m, 3H), 7.67 (d, J = 8.6 Hz, 1H), 7.37-7.47 (m, 3H), 7.26-7.35 (m, 2H), 7.20 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 8.6 Hz, 2H), 5.44 (s, 2H), 4.13 (q, J = 7.0 Hz, 2H), 3.75-3.86 (m, 5H), 3.70 (br.s., 2H), 2.35 (br.s., 6H), 1.46 (t, J = 7.0 Hz, 3H) ES- LCMS m/z 612.2 (M+H).

Step 6: N- (4-((Dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-yloxy)- 1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide hydrochloride

Containing N- (4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-) at room temperature Add HCl (1,4-(4-(4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (5.8 g, 7.30 mmol) in DCM (50 mL) two Alkane solution, 5 mL, 20.00 mmol). The solution was stirred at 20 ° C for 30 min. The solution was concentrated in vacuo to give a crude material. Purification by preparative HPLC The crude product (MeCN / H ₂ O as the eluent, acidic conditions) to give an off-white solid of N - (4 - ((dimethylamino) methyl) -3- (trifluoromethyl) Phenyl)-2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide hydrochloride (1.5 g , 2.78 mmol, 38.1% yield). TLC (DCM / MeOH = 5:1, _Rf = 0.3): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.21. (d, J = 1.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H) , 7.75 (d, J = 8.4 Hz, 1H), 7.36-7.53 (m, 5H), 4.50 (s, 2H), 4.20 (q, J = 7.0 Hz, 2H), 3.87 (s, 2H), 2.95 ( s, 6H), 1.50 (t, J = 7.0 Hz, 3H); ES-LCMS m/z 492.2 (M+H).

Example 18: N- (3,4-Dichlorophenyl)-2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluoro Phenyl)acetamide

Step 1: 2- (4-bromo-2-fluorophenyl) - N - (3,4- dichlorophenyl) acetyl amine

In DCM (20 mL) solution containing 2-(4-bromo-2-fluorophenyl)acetic acid (144 mg, 0.617 mmol), 3,4-dichloroaniline (100 mg, 0.617 mmol) and HATU (704 mg, 1.852 mmol) Et ₃ N (0.258 mL, 1.852 mmol) was added dropwise. The mixture was then stirred under nitrogen at 20 ° C for 3 h. LCMS analysis indicated that after the starting material had disappeared, solvent was evaporated in vacuo. The crude product was then dissolved in DCM, washed with H ₂ O and brine. The organic layer was evaporated to dryness, and the crude product was purified by silica gel column chromatography (PE/EA=100/1 to 8/1) to yield the product 2-(4-bromo-2-fluorophenyl)- N- (3,4-dichlorophenyl)acetamide (190 mg, 0.419 mmol, 67.8% yield): ¹ H NMR: (400 MHz, CD ₃ OD) δ 10.25 (br.s, 1H), 7. s, 1H), 7.44 (s, 2H), 7.28-7.37 (m, 3H), 3.74 (s, 2H); ES-LCMS: m/z 377.9 (M+H).

Step 2: N- (3,4-Dichlorophenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)- 2-fluorophenyl)acetamide

Containing 2- (4-bromo-2-fluorophenyl) - N - (3,4- dichlorophenyl) acetyl amine (60mg, 0.159mmol), 3- ethoxy-2 - ((4- Methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (61.3 mg, 0.159 mmol) ) with 1,4-two of Cs ₂ CO _{3 (} 156mg, 0.477mmol) A full amount of PdCl ₂ (dppf) (11.64 mg, 0.016 mmol) was added in one portion of a solution of aq. (3 mL) and H ₂ O (1 mL). The mixture was stirred under a microwave at 130 ° C for 30 min. After LCMS analysis indicated that the starting material had disappeared, the mixture was filtered. The filtrate was concentrated and evaporated to dryness, the crude product was dissolved in DCM, washed with H ₂ O and brine. The crude product was purified by preparative TLC (DCM /MeOH = 40/1) to yield the product N- (3,4-dichlorophenyl)-2-(4-(5- ethoxy-6-( 4-methoxybenzyloxy)pyridin-3-yl)-2-fluorophenyl)acetamide (60.0 mg, 0.084 mmol, 52.7% yield): ¹ H NMR: (400 MHz, CD ₃ OD ) δ 7.95 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 1.8 Hz, 1H), 7.45 (s, 3H), 7.43 - 7.37 (m, 5H), 6.91 (d, J = 8.6 Hz) , 2H), 5.37 (s, 2H), 4.15 (m, 3H), 3.79 (s, 4H), 1.42 (t, J = 7.0 Hz, 3H); ES-LCMS: m/z 435 (M-120) .

Step 3: N- (3,4-Dichlorophenyl)-2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluoro Phenyl)acetamide

Containing N- (3,4-dichlorophenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2 A solution of fluorophenyl)acetamide (60 mg, 0.108 mmol) in EtOAc (MeOH,EtOAc. LCMS analysis indicated that after the starting material had disappeared, solvent was evaporated in vacuo. The crude product was purified by preparative HPLC to give the pure product N- (3,4-dichlorophenyl)-2-(4-(5-ethoxy-6-s-oxy-1,6-dihydropyridine)- 3-yl)-2-fluorophenyl)acetamide (14.72 mg, 0.034 mmol, 31.3% yield): ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.92 (s, 1H), 7.45 (s, 2H), 7.41 (d, J = 7.6 Hz, 1H), 7.38-7.32 (m, 3H), 7.28-7.25 (m, 1H), 7.27 (d, J = 2.0 Hz, 1H), 4.14 (m, 2H) ), 3.79 (s, 2H), 1.47 (t, J = 7.0 Hz, 3H); ES-LCMS: m/z 435.0 (M+H).

Example 19: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (5- (1,1 , 1-trifluoro-2-methylpropan-2-yl) Zin-3-yl)acetamide

Step 1: 2- (4-bromo-2-fluorophenyl) - N - (5- (1,1,1- trifluoro-2-methylpropan-2-yl) iso Zin-3-yl)acetamide

Add 5-(1,1,1-trifluoro-2-methylpropane-2-) to a mixture of 2-(4-bromo-2-fluorophenyl)acetic acid (100 mg, 0.429 mmol) Base) Oxadiazol-3-amine (92mg, 0.472mmol), HATU ( 245mg, 0.644mmol) and _{Et 3 N (0.179mL, 1.287mmol)} . The mixture was then stirred at 25 ° C for 12 h. The mixture was concentrated and the crude product was purified by preparative TLC (PE / EA = 2: 1, Rf = 0.4) yielded the yellow oil of 2- (4-bromo-2-fluorophenyl) - N - (5- ( 1,1,1-trifluoro-2-methylpropan-2-yl) Zyridin-3-yl)acetamide (50 mg, 0.109 mmol, 25.4% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.12 (s., 1H) 7.35-7.27 (m, 2H) 7.23-7. (m, 1H) 6.95 (s, 1H) 3.72 (s, 2H) 1.55 (s, 6H); ES-LCMS m/z 411 (M+2).

Step 2: 2- (4- (5-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (5- ( 1,1,1-trifluoro-2-methylpropan-2-yl) Zin-3-yl)acetamide

3-oxo-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2 under nitrogen atmosphere - dioxaborolan-2-yl) pyridine (60mg, 0.156mmol), 2- ( 4- bromo-2-fluorophenyl) - N - (5- (1,1,1- trifluoro - 2-methylpropan-2-yl)iso Zyridin-3-yl)acetamide (63.7 mg, 0.156 mmol) in H ₂ O (1 mL) and 1,4-di Cs ₂ CO ₃ (101 mg, 0.311 mmol) and PdCl ₂ (dppf) (11.40 mg, 0.016 mmol) were added to the mixture. The mixture was then stirred and irradiated in a microwave oven at 120 ° C for 30 min. The mixture was concentrated and extracted with EA. The combined organic layers were concentrated, and the crude material was purified by preparative TLC (PE/EA=2:1, _Rf = 0.5) to yield 2-(4-(5-ethoxy-6-(4) - methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (5- (1,1,1- trifluoro-2-methylpropan-2-yl) iso Zyridin-3-yl)acetamide (20 mg, 0.031 mmol, 19.9% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ: 7.97 (d, J = 2.0 Hz, 1H), 7.47 (d, J =2.0 Hz, 1H), 7.46-7.37 (m, 5H), 6.97-7.89 (m, 3H), 5.39 (s, 2H), 4.17 (q, J = 6.8 Hz, 2H), 3.85 (s, 2H) , 3.83 - 3.79 (m, 3H), 1.60 (s, 6H), 1.45 (t, J = 7.0 Hz, 3H); ES-LCMS m/z 588 (M+1).

Step 3: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (4- (3- hydroxy -2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

A mixture of 2- (4- (5-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (5- (1 , 1,1-trifluoro-2-methylpropan-2-yl) Zyrid-3-yl)acetamide (20 mg, 0.034 mmol) with HCl (4M II) A mixture of the alkane solution, 20 mL) was stirred at 25 ° C for 2 h. The mixture was concentrated and the crude product was purified by preparative HPLC (MeCN/H ₂ O as solvent, acidic) to yield 2-(4-(5- ethoxy-6- s s s - dihydro-pyridin-3-yl) -2-fluorophenyl) - N - (5- (1,1,1- trifluoro-2-methylpropan-2-yl) iso Oxazol-3-yl)acetamide (7.9 mg, 0.017 mmol, 49.7% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ: 7.42-7.36 (m, 1H), 7.35 (s, 2H), 7.29 (d, J = 2.2 Hz, 1H), 7.22 (d, J = 2.2 Hz, 1H), 6.87 (s, 1H), 4.12 (q, J = 7.0 Hz, 2H), 3.81 (s, 2H), 1.56 (s, 6H), 1.46 (t, J = 6.8 Hz, 3H); ES-LCMS m/z 468 (M+1).

Example 20: (2-fluorophenyl 4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)) 2- - N - (4- (2- hydroxy Ethoxy)-3-(trifluoromethyl)phenyl)acetamide

Step 1: N- (4-(2-(Benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2-fluorophenyl)acetamide

2-(4-Bromo-2-fluorophenyl)acetic acid (600 mg, 2.57 mmol), EDC (592 mg, 3.09 mmol), HOBt (473 mg, 3.09 mmol), Et ₃ N (1.056 mL, 7.72 mmol) The DCM (10 mL) suspension was stirred at room temperature for 2 h. The mixture was extracted with DCM (2 x 50 mL). The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product is purified by preparative TLC to give N- (4-(2-(phenylmethyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2-fluoro Phenyl)acetamide (450 mg, 0.496 mmol, 19.3% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.83-7.82 (d, J = 2.4 Hz, 1H), 7.71-7.68 (dd, J = 8.8, 2.4 Hz, 1H), 7.34 - 7.29 (m, 1H), 7.15 - 7.13 (d, J = 8.8 Hz, 1H), 4.60 (s, 2H), 4.23 (t, J = 4.8 Hz, 2H) 3.83 (t, J = 4.6 Hz, 2H), 3.71 (s, 2H); ES-LCMS m/z 526 (M+H).

Step 2: N- (4-(2-(Benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(2-fluoro-4-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide

Taking N- (4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2-fluorophenyl)acetamide ( 300 mg, 0.570 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) (145mg, 0.570mmol), PdCl ₂ (dppf) (41.7mg, 0.057mmol), KOAc (112mg, 1.140mmol) 1,4-two The alkane (10 mL) suspension was heated to 100 ° C for 120 min under nitrogen atmosphere. The mixture was concentrated and the residue was extracted using DCM (20 mL x 2). The mixture was then concentrated and the residue was extracted using DCM (20 mL x 2). The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (EA/PE = 1:1, Rf = 0.5) to yield N- (4-(2-(phenylmethyloxy)ethoxy)-3-(trifluoromethyl)benzene 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamidamine 300mg, 0.314mmol, 55.1% ^{yield): 1 H NMR (400MHz,} CD 3 OD) δ 7.84 (d, J = 2.6Hz, 1H), 7.70 (dd, J = 9.0,2.4Hz, 1H), 7.51 ( d, J = 7.5 Hz, 1H), 7.42 - 7.21 (m, 7H), 7.14 (d, J = 9.0 Hz, 1H), 4.29 - 4.19 (m, 2H), 3.89 - 3.82 (m, 2H), 3.76 (s, 2H), 1.33 (s, 12H); ES-LCMS m/z 721 (M+H).

Step 3: N- (4-(2-(Benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-((5-ethoxy-6-) (4-methoxybenzyl)oxypyridin-3-yl)oxy)-2-fluorophenyl)acetamide

2-(Benzyloxy)-4-ethoxy-5-iodopyridine (80 mg, 0.225 mmol), N- (4-(2-(benzyloxy)ethoxy)-3-() Trifluoromethyl)phenyl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene Ethylamine (129 mg, 0.225 mmol), PdCl ₂ (dppf) (16.48 mg, 0.023 mmol), Cs ₂ CO ₃ (73.4 mg, 0.225 mmol) 1,4-two Dioxane (5mL) and H ₂ O (1mL) The suspension was heated to 100 ℃ 20min in a microwave to the gas mask under N _2. The mixture was then concentrated and the residue was extracted using DCM (20 mL x 2). The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (EA/PE = 1:1, Rf = 0.5) to yield 2-(4-(6-(phenylmethyloxy)-4-ethoxypyridin-3-yl)-2 -fluorophenyl)-N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)acetamide (60 mg, 0.054 mmol, 24.1% yield) : ¹ H NMR (400 MHz, CD ₃ OD) δ 7.95 (s., 1H), 7.85-7.84 (d, J = 2.4 Hz, 1H), 7.74-7.71 (dd, J = 8.8, 2.4 Hz, 1H), 7.44-7.42 (m, 2H), 7.38-7.24 (m, 10H), 7.16-7.14 (d, J = 8.8 Hz, 1H), 6.48 (s, 1H), 5.35 (s, 2H), 4.61 (s, 2H), 4.23 (t, J = 4.6 Hz, 2H), 4.15-4.10 (m, 3H), 3.84 (t, J = 4.6 Hz, 2H), 3.77 (s, 2H), 3.66-3.65 (m, 1H) ), 3.55-3.54 (m, 1H), 1.36 (t, J = 7.2 Hz, 3H); ES-LCMS m/z 721 (M+H).

Step 4: 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (4- (2- hydroxy Ethoxy)-3-(trifluoromethyl)phenyl)acetamide

A mixture of 2- (4- (6- (benzyl oxy) -4-ethoxy-pyridin-3-yl) -2-fluorophenyl) - N - (4- (2- ( phenylmethyl oxy) ethoxy) -3- (trifluoromethyl) phenyl) acetyl amine (60mg, 0.089mmol), Pd / C (9.46mg, 0.089mmol) of MeOH (10mL) in a mixture of H ₂ gas and the mask 25 ℃ Stir under 16h. The mixture is then filtered, the filtrate is concentrated and the residue obtained is purified by preparative HPLC to yield 2-(4-(4-ethoxy-6-s-oxyl-1,6-dihydropyridin-3-yl)-2 - fluorophenyl) - N - (4- (2- hydroxyethoxy) -3- (trifluoromethyl) phenyl) acetyl amine (17.76mg, 0.034mmol, 38.8% yield): ¹ H NMR (400MHz, CD ₃ OD) δ 7.83 (d, J = 2.4 Hz., 1H), 7.73-7.70 (m, 1H), 7.35-7.29 (m, 2H), 7.42 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.23 - 7.21 (m, 2H), 7.17 - 7.14 (d, J = 4.6 Hz, 1H), 6.03 (s, 1H), 4.13-4.11 (m, 4H), 3.87 (t , J = 5.0 Hz, 2H), 3.76 (s, 2H), 1.37 (t, J = 7.0 Hz, 3H); ES-LCMS m/z 495 (M+H).

Example 21: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (4 - ( (4- Ethyl pipe -1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide dihydrochloride

Step 1: 2- (4-bromo-2-fluorophenyl) - N - (4 - ( (4- ethylpiperazin -1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide

Take 4-((4-ethylperidazole) A suspension of -1-yl)methyl)-3-(trifluoromethyl)aniline (247 mg, 0.858 mmol) in DCM (35 mL) was added to 2-(4-bromo-2-fluorophenyl)acetic acid (200 mg) , 0.858 mmol) in DCM (35 mL). Was added HOBt (197mg, 1.287mmol), EDC (247mg, 1.287mmol) and _{Et 3 N (0.359mL, 2.57mmol)} , the mixture was stirred at 26 ℃ 3h. The solution was then concentrated, and dissolved points between EA and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by column chromatography (PE/EA = 10/1). TLC taken by the determination of the product-containing fractions were all dissolved (PE / EA = 5/1 , R f = 0.6) were combined and concentrated to give a pale yellow solid of 2- (4-bromo-2-fluorophenyl) - N - ( 4-((4-ethylperidazole) 1-yl) methyl) -3- (trifluoromethyl) phenyl) acetyl amine (413mg, 0.822mmol, 96.0% ^{yield): 1 H NMR (400MHz,} CD3OD) δ 7.98-7.91 (m, 1H), 7.79-7.67 (m, 2H), 7.40-7.27 (m, 3H), 3.74 (s, 2H), 3.61 (s, 2H), 2.58-2.39 (m, 11H), 1.09 (s, 4H) ;ES-LCMS m/z 502.0 (M+H).

Step 2: 2- (4- (5-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (4- ( (4-ethylperidazole -1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide

A mixture of 2- (4-bromo-2-fluorophenyl) - N - (4 - ( (4- ethylpiperazin -1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide (413 mg, 0.822 mmol) of 1,4-di Add a suspension of alkane (3 mL) and H ₂ O (1 mL) to 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetra 1,4-dimethyl-1,3,2-dioxaborolan-2-yl)pyridine (317 mg, 0.822 mmol) Alkane (3 mL) in H ₂ O (1 mL) solution. PdCl ₂ (dppf) (60.2 mg, 0.082 mmol) and Cs ₂ CO ₃ (536 mg, 1.644 mmol) were added, and the mixture was subjected to a microwave at 110 ° C for 30 minutes. The mixture was cooled to room temperature. The solution was then concentrated, and dissolved points between EA and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (PE / EA = 1/ 1, R f = 0.5) yielded the pale yellow solid of 2- (4- (5-ethoxy-6 - ((4-methoxy-benzyloxy yl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (4 - ( (4- ethylpiperazin -1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide (405 mg, 0.595 mmol, 72.4% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.02-7. m, 2H), 7.82-7.64 (m, 2H), 7.60-7.30 (m, 6H), 6.98-6.80 (m, 2H), 5.34 (s, 2H), 4.18-4.04 (m, 2H), 3.84 3.72 (m, 4H), 3.68-3.57 (m, 2H), 2.91-2.38 (m, 10H), 1.47-1.31 (m, 3H), 1.14 (s, 3H); ES-LCMS m/z 681.3 (M +H).

Step 3: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (4 - ( (4- Ethyl pipe -1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide dihydrochloride

A mixture of 2- (4- (5-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (4 - ( ( 4-ethylperidazole A suspension of -1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamidamine (400 mg, 0.588 mmol) in MeOH (10 mL) was added to Pd/c (62.5mg, 0.588mmol) In a solution of MeOH (10 mL). The mixture was hydrogenated at 26 ° C for 2 h. The solution was then filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/H ₂ O as eluting solvent, acidic conditions) to yield 2-(4-(5-ethoxy-6-s. pyridin-3-yl) -2-fluorophenyl) - N - (4 - ( (4- ethylpiperazin 1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamidine dihydrochloride (40.71 mg, 0.064 mmol, 10.9% yield). TLC (DCM / MeOH = 10/ 1, R f = 0.4): 1 H NMR (400MHz, CD 3 OD) δ 8.22 (d, J = 1.8Hz, 1H), 8.05 (d, J = 8.6Hz, 1H) , 7.95 (dd, J = 8.6, 1.8 Hz, 1H), 7.75-7.61 (m, 2H), 7.55-7.37 (m, 3H), 4.63-4.50 (m, 2H), 4.27 (q, J = 6.9 Hz) , 2H), 3.96-3.53 (m, 10H), 3.37-3.31 (m, 2H), 1.56-1.45 (m, 3H), 1.39 (t, J = 7.3 Hz, 3H); ES-LCMS m/z 561.1 (M+H).

Example 22: N -(2,5-Difluorophenyl)-2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluoro Phenyl)acetamide

Step 1: 2,5-difluoroaniline

Pd/C (66.9 mg, 0.629 mmol) was added portion wise in MeOH (20 mL) EtOAc. The mixture was then stirred at 20 ° C for 1 h under H ₂ atmosphere. Analysis of TLC (PE/EA = 3/1) showed that after the starting material had disappeared, the mixture was filtered. The filtrate was concentrated to give the desired product 2,5-difluoroaniline (338 mg, 2.61 mmol, 83% yield). ^{1 H NMR: (400MHz, CDCl} 3) δ 6.94-6.88 (m, 1H), 6.50-6.46 (m, 1H), 6.40-6.31 (m, 1H), 3.82 (br.s., 2H).

Step 2: 2- (4-bromo-2-fluorophenyl) - N - (2,5- difluorophenyl) acetyl amine

Add Et ₃ N in portions in a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (180 mg, 0.775 mmol) and 2,5-difluoroaniline (100 mg, 0.775 mmol) in DCM (20 mL) 0.324 mL, 2.324 mmol) with HATU (884 mg, 2.324 mmol). The mixture was then stirred at 20 ° C for 3 h. LCMS analysis indicated that after the starting material had disappeared, solvent was evaporated in vacuo. The crude product was then dissolved in DCM, washed with H ₂ O and brine. The organic layer was evaporated to dryness. Silica The crude product was purified by column chromatography (PE / EA 100/1 to 10/1) to give 2- (4-bromo-2-fluorophenyl) - N - (2,5- difluorophenyl Ethylamine (103 mg, 0.276 mmol, 35.6% yield). ^{1 H NMR: (400MHz, CD} 3 OD) δ 7.87-7.82 (m, 1H), 7.39-7.26 (m, 3H), 7.20-7.13 (m, 1H), 6.90-6.82 (m, 1H), 3.83 ( s, 2H); ES-LCMS: m/z 343.9 (M+H).

Step 3: N- (2,5-Difluorophenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)- 2-fluorophenyl)acetamide

Containing 2- (4-bromo-2-fluorophenyl) - N - (2,5- difluorophenyl) acetyl amine (40mg, 0.116mmol), 3- ethoxy-2 - ((4- Methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (44.8 mg, 0.116 mmol) ) with 1,4-two of Cs ₂ CO ₃ (114 mg, 0.349 mmol) A full amount of PdCl ₂ (dppf) (8.51 mg, 0.012 mmol) was added in one portion of a solution of aq. (3 mL) and H ₂ O (1 mL). The mixture was then stirred under a microwave at 110 ° C for 30 min. After LCMS analysis indicated that the starting material had disappeared, the mixture was filtered. The filtrate was concentrated and evaporated to dryness, the crude product was dissolved in DCM, and washed with H ₂ O and brine. The crude product is then purified by preparative TLC to give N- (2,5-difluorophenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl))oxy) Pyridin-3-yl)-2-fluorophenyl)acetamide (45.0 mg, 0054 mmol, 46.1% yield). ^{1 H NMR: (400MHz, CD} 3 OD) δ 7.96 (d, J = 2.0Hz, 1H), 7.88 (d, J = 9.6Hz, 1H), 7.46 (d, J = 2.0Hz, 1H), 7.36- 7.44 (m, 5H), 7.18 (m, 1H), 6.91 (d, J = 8.6 Hz, 2H), 6.87 (br.s., 1H), 5.37 (s, 2H), 4.15-4.13 (m, 2H) ), 3.88 (s, 2H), 3.79 (s, 3H), 1.43 (t, J = 7.0 Hz, 3H); ES-LCMS: m/z 403.0 (M-120+H).

Step 4: N- (2,5-Difluorophenyl)-2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluoro Phenyl)acetamide

Containing N- (2,5-difluorophenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2 A solution of fluorophenyl)acetamide (45 mg, 0.086 mmol) in EtOAc (MeOH (EtOAc) LCMS analysis showed that after the starting material had disappeared, the solvent was removed in vacuo and the crude product was purified by preparative HPLC to yield pure product N- (2,5-difluorophenyl)-2-(4-(5-ethoxy) -6-6-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide (5.83 mg, 0.014 mmol, 16.8% yield): ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.86 (broad s, 1H), 7.43-7.37 (m, 5H), 7.20-7.13 (m, 1H), 6.86 (t, J = 8.4 Hz, 1H), 4.20-4.15 (m, 2H) ), 3.88 (s, 2H), 1.48 (t, J = 7.0 Hz, 3H); ES-LCMS: m/z 403.0 (M+H).

Examples 23-26 (Table 1) are similar to those described in Example 17, but using 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Intermediate 1), 2-(4-bromo-2-fluorophenyl)acetic acid (intermediate) 4), and various anilines are prepared as starting materials.

Example 27: 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (1,1 , 1-trifluoro-2-methylpropan-2-yl) Oxazol-5-yl)acetamide

Step 1: 2-Chloro-4-ethoxypyridine

Sodium ethoxide (25.8 g, 378 mmol) was added portionwise over a mixture of EtOAc (20 mL, EtOAc. The mixture was stirred at 25 ° C for 10 h. The mixture was filtered and the filtrate was concentrated. The crude product was purified by column chromatography (PE/EA = 5:1). All the fractions containing the product (PE/EA = 5:1, _Rf = 0.6) were judged by TLC to be combined and concentrated to give 2-chloro-4-ethoxypyridine as a pale yellow solid (13 g, 71.9 mmol, 57 % yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.18 (d, J = 5.2 Hz, 1H), 6.82 (d, J = 2.4 Hz, 1H), 6.73 (dd, J = 2.0, 6.0 Hz, 1H), 4.09 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H); ES-LCMS m/z 158 (M+H).

Step 2: 5-Bromo-2-chloro-4-ethoxypyridine

2-chloro-4-ethoxy-pyridine (13g, 82mmol) and H ₂ SO ₄ was added NBS (17.62g, 99mmol) (40mL , 750mmol) mixture. The mixture was then stirred at 60 ° C for 10 h. After cooling to room temperature, the mixture was poured into cold water (300 mL). The mixture was extracted using EA (200 mL x 2). The combined organic layer with saturated NaHCO ₃ solution (200mL x2) and washed with concentrated. The crude product was purified by column chromatography (PE/EA = 15:1). All the fractions containing the product (PE/EA = 5:1, _Rf = 0.6) were judged by TLC to be combined and concentrated to give 5-bromo-2-chloro-4-ethoxypyridine (8.5 g, 26.3mmol, 32% yield): ¹ H NMR (400MHz, CDCl ₃ ) δ 8.32 (s, 1H), 6.79 (s, 1H), 4.16 (q, J = 6.8 Hz, 2H), 1.50 (t, J = 6.8 Hz, 3H); ES-LCMS m/z 238 (M+3).

Step 3: 5-Bromo-4-ethoxy-2-((4-methoxybenzyl)oxy)pyridine

5-Bromo-2-chloro-4-ethoxypyridine (8 g, 33.8 mmol), Cs ₂ CO ₃ (33.1 g, 101 mmol) and (4-methoxyphenyl)methanol (5.37 g, 38.9 mmol) The mixture of DMF (100 mL) was stirred at 120 ° C for 12 h. The mixture was then concentrated. The residue was added to DCM (150 mL). The mixture was filtered and the filtrate was concentrated. The crude product was purified by column chromatography (PE/EA = 8:1). All the fractions containing the product (PE/EA = 5:1, Rf = 0.4) were judged by TLC to be combined and concentrated to give 5-bromo-4-ethoxy-2-((4-methoxy) as a yellow solid. Benzyl)oxy)pyridine (5 g, 12.57 mmol, 37% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.05 (s, 1H), 7.32 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.17 (s, 1H), 5.18 (s, 2H), 4.02 (q, J = 6.8 Hz, 2H), 3.74 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H); ES-LCMS m/z 338 (M+H).

Step 4: 2- (2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) - N - ( 3-(1,1,1-trifluoro-2-methylpropan-2-yl)iso Oxazol-5-yl)acetamide

Under nitrogen, in the presence of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborane) pentane) (279mg, 1.100mmol) and 2- (4-bromo-2-fluorophenyl) - N - (3- (1,1,1- trifluoro-2-methylpropan-2-yl) iso Benzene-5-yl)acetamide (300 mg, 0.733 mmol) of 1,4-two Dioxane (50mL) was added a mixture of KOAc (216mg, 2.2mmol) and _{PdCl 2 (dppf) (26.8mg,} 0.037mmol). The mixture was then stirred at 100 ° C for 5 h. The mixture was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC (PE / EA = 3: 1 , R f = 0.5), to yield a yellow solid of 2- (2-fluoro-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) phenyl) - N - (3- (1,1,1- trifluoro-2-methylpropan-2-yl) iso Imidazole-5-yl)acetamide (230 mg, 0.403 mmol, 55% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (s, 1H), 7.63-7.48 (m, 2H), 7.35-7.29 (m, 1H), 6.43 (s, 1H), 3.84-3.76 (m, 2H), 1.53-1.49 (m, 6H), 1.34 (s, 9H); ES-LCMS m/z : 457 (M+H ).

Step 5: 2- (4- (4-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (3- ( 1,1,1-trifluoro-2-methylpropan-2-yl) Oxazol-5-yl)acetamide

5-(Bromo-4-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (74.1 mg, 0.219 mmol) and 2-(2-fluoro-4) under nitrogen atmosphere - (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) - N - (3- (1,1,1- trifluoro -2-methylpropan-2-yl)iso Zol-5-yl)acetamide (100 mg, 0.219 mmol) in water (1 mL) with 1,4-di Cs ₂ CO ₃ (143 mg, 0.438 mmol) and PdCl ₂ (dppf) (16.04 mg, 0.022 mmol) were added to a mixture of hexanes (3 mL). The mixture was then stirred and irradiated in a microwave oven at 120 ° C for 20 min. The mixture was then concentrated. The crude product was purified by preparative TLC (PE / EA = 2: 1, R f = 0.4) yielded the off-white solid of 2- (4- (4-ethoxy-6 - ((4-methoxybenzyl ) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (3- (1,1,1- trifluoro-2-methylpropan-2-yl) iso Imidazole-5-yl)acetamide (70 mg, 0.071 mmol, 33% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.40-7.34 (m, 2H), 7.30-7.17 (m, 4H), 6.92-6.88 (m, 2H), 6.45 (s, 1H), 6.38 (d, J = 4.0 Hz, 1H), 5.27 (s, 2H), 4.13-4.10 (m, 2H), 3.83-3.82 (m, 2H), 3.79-3.77 (m, 3H), 1.53 (s, 6H), 1.37 (t, J = 6.8 Hz, 3H); ES-LCMS m/z : 588 (M+H).

Step 6: 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (1,1 , 1-trifluoro-2-methylpropan-2-yl) Oxazol-5-yl)acetamide

A mixture of 2- (4- (4-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (3- (1 , 1,1-trifluoro-2-methylpropan-2-yl) A mixture of oxazol-5-yl)acetamide (70 mg, 0.119 mmol) and TFA (10%EtOAc. The mixture was concentrated. The crude product was purified by preparative HPLC (MeCN/H ₂ O as eluting solvent, basic conditions) to yield 2-(4-(4-ethoxy-6-s-oxyl-1,6-dihydro) as a white solid. pyridin-3-yl) -2-fluorophenyl) - N - (3- (1,1,1- trifluoro-2-methylpropan-2-yl) iso Imidazole-5-yl)acetamide (24.61 mg, 0.051 mmol, 43% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.39-7.32 (m, 1H), 7.26-7.18 (m, 1H) , 6.37 (s, 1H), 5.99 (s, 1H), 4.10 (q, J = 6.8 Hz, 2H), 3.82 (s, 2H), 1.53 (s, 6H), 1.37 (t, J = 7.2 Hz, 3H); ES-LCMS m/z : 468 (M+H).

Example 28: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (1,1 , 1-trifluoro-2-methylpropan-2-yl) Oxazol-5-yl)acetamide

Step 1: 3-bromo-5-ethoxypyridine

A solution of 5-bromopyridin-3-ol (70 g, 402 mmol), K ₂ CO ₃ (111 g, 805 mmol), ethyl iodide (69.0 g, 443 mmol) in DMF (900 mL) The mixture was then concentrated, EtOAc (EtOAc EtOAc (EtOAc) % yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.19-8.17 (m, 2H), 7.60-7.59 (m, 1H), 4.13-4.07 (m, 2H), 1.40 (t, J = 7.0) Hz, 3H); ES-LCMS m/z 202 (M+H).

Step 2: 3-Bromo-5-ethoxypyridine-1-oxide

m- CPBA (67.9 g, 393 mmol) was added slowly over a 30 min period over EtOAc over EtOAc. After the resulting solution was stirred for 15 h, the mixture was washed with a Na ₂ S ₂ O ₃ solution and extracted with DCM (600 mL). The combined organic layer with saturated NaHCO ₃ (300mL), washed with brine (300 mL), dried over sodium sulfate, filtered, and concentrated to yield 3-bromo-5-ethoxy-1-oxide (40g, 165mmol, 63 % yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.19-8.18 (m, 1H), 8.08-8.07 (m, 1H), 7.50-7.49 (m, 1H), 4.17 - 4.15 (d, J = 8.8 Hz, 2H), 1.43 (t, J = 7.0 Hz, 3H); ES-LCMS m/z 217 (M+H).

Step 3: 5-Bromo-2-chloro-3-ethoxypyridine

At 0 deg.] C, containing 3-bromo-5-ethoxy-1-oxide (40g, 183mmol) of DCM (200mL) solution was added slowly over 30 minutes to POCl ₃ (159mL, 1701mmol). The resulting solution was then allowed to warm to 45 ° C and stirred for 15 h. The mixture was concentrated, adjusted to pH = 9-10 using a 10% NaOH solution, extracted with DCM (300 mL x 2), dried over sodium sulfate, filtered, and concentrated, and the crude product was purified by fluorite column chromatography (10) % EA: 90% PE, 800g meteorite column). All the fractions (EA: PE = 1:5, R _f = 0.6) containing the product were judged by TLC to be combined and concentrated to give 5-bromo-2-chloro-3-ethoxypyridine (30 g, 60.9mmol, 33% yield): ¹ H NMR (400MHz, CD ₃ OD) δ 8.00-7.99 (d, J = 2.0Hz, 1H), 7.65-7.64 (d, J = 2.0Hz, 1H), 4.17- 4.12 (m, 2H), 1.44 (t, J = 7.0 Hz, 2H); ES-LCMS m/z 235 (M+H).

Step 4: 5-Bromo-3-ethoxy-2-((4-methoxybenzyl)oxy)pyridine

To a mixture of (4-methoxyphenyl)methanol (16.71 g, 121 mmol) in DMF (300 mL) After the mixture was stirred for 30 min, EtOAc (EtOAc m.) A mixture of H ₂ O (20mL) quenched, extracted with DCM (400mL x 2), dried over sodium sulfate, filtered, and concentrated and purified by column chromatography mass (10% EA generation of residues: 90% PE, 360g Meteorite column). All the fractions containing the product (EA: PE = 1:5, R _f = 0.5) were judged by TLC to be combined and concentrated to give 5-bromo-3-ethoxy-2-((4-methoxy) as a white solid. Benzomethyl)oxy)pyridine (36 g, 74.5 mmol, 68% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.71 (d, J = 2.0 Hz, 1H), 7.36-7.31 (m, 3H) ), 6.89-6.87 (m, 2H), 5.27 (s, 2H), 4.05-4.00 (m, 2H) 3.77 (s, 3H), 2.37 (d, J = 7.0 Hz, 3H); ES-LCMS m/ z 338 (M+H).

Step 5: 3-Ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Cyclopentan-2-yl)pyridine

Containing 5-bromo-3-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (10 g, 29.6 mmol), 4, 4, 4' in a nitrogen atmosphere at 20 ° C , 4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolane) (8.26 g, 32.5 mmol) with KOAc (7.25 g, 73.9mmol) of 1,4-two A full amount of PdCl ₂ (dppf) (1.082 g, 1.478 mmol) was added in one portion of the alkane (250 mL) solution. The reaction mixture was stirred at 100 ° C for 3 h. The mixture was filtered and the filtrate was concentrated in vacuo to give crude material. The crude product was purified by column chromatography (PE/EA = 10:1). All the fractions containing the product (PE/EA = 10:1, R _f = 0.6) were judged by TLC to be combined and concentrated to give 3-ethoxy-2-((4-methoxybenzyl) as a white solid. Oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (9.2 g, 23.88 mmol, 81% yield) : ¹ H NMR (400 MHZ, CDCl ₃ ) δ 8.10 (s, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.33 (s, 1H), 6.88-6.85 (m, 2H), 5.45 (s, 2H), 4.11-4.06 (m, 2H), 3.78 (s, 3H), 1.43 (t, J = 7.0 Hz, 3H), 1.33 (s, 12H); ES-LCMS m/z 386.0 (M+H) .

Step 6: 2- (4- (5-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (3- ( 1,1,1-trifluoro-2-methylpropan-2-yl) Oxazol-5-yl)acetamide

3-oxo-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2 under nitrogen atmosphere - dioxaborolan-2-yl) pyridine (200mg, 0.519mmol) and 2- (4-bromo-2-fluorophenyl) - N - (3- (1,1,1- trifluoro - 2-methylpropan-2-yl)iso Zol-5-yl)acetamide (212 mg, 0.519 mmol) in water (1 mL) with 1,4-di Cs ₂ CO ₃ (338 mg, 1.038 mmol) and PdCl ₂ (dppf) (38.0 mg, 0.052 mmol) were added to a mixture of aq. The mixture was then stirred and irradiated in a microwave oven at 120 ° C for 20 min. The mixture was then concentrated. The crude product was purified by preparative TLC (PE / EA = 2: 1, R f = 0.4) yielded the off-white solid of 2- (4- (5-ethoxy-6 - ((4-methoxybenzyl ) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (3- (1,1,1- trifluoro-2-methylpropan-2-yl) iso Imidazole-5-yl)acetamide (100 mg, 0.121 mmol, 23% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.42-7.28 (m, 5H), 7.27-7.21 (m, 2H), 6.92-6.84 (m, 2H), 6.36 (s, 1H), 4.50 (s, 2H), 4.11 (d, J = 6.8 Hz, 2H), 3.82 (s, 2H), 3.79-3.75 (m, 3H) , 1.52 (s, 6H), 1.45 (t, J = 7.2 Hz, 3H); ES-LCMS m/z 468 (M-119).

Step 7: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (1,1 , 1-trifluoro-2-methylpropan-2-yl) Oxazol-5-yl)acetamide

A mixture of 2- (4- (5-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (3- (1 , 1,1-trifluoro-2-methylpropan-2-yl) The mixture of oxazol-5-yl)acetamide (100 mg, 0.170 mmol) and TFA (10% DCM solution, 100 mL) was stirred at 25 ° C for 2 h. The mixture was then concentrated. The crude product was purified by preparative HPLC (MeCN/H ₂ O as eluting solvent, acidic conditions) to yield 2-(4-(5-ethoxy-6-s-oxyl-1,6-dihydropyridine) as a white solid. 3-yl) -2-fluorophenyl) - N - (3- (1,1,1- trifluoro-2-methylpropan-2-yl) iso Oxazol-5-yl)acetamide (28.35 mg, 0.060 mmol, 36% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.45-7.30 (m, 4H), 7.25 (d, J = 1.6 Hz) , 1H), 6.36 (s, 1H), 4.12 (q, J = 6.8 Hz, 2H), 3.82 (s, 2H), 1.52 (s, 6H), 1.46 (t, J = 6.8 Hz, 3H); - LCMS m/z 468 (M+H).

Example 29: 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (5- methyl Base-1,3,4- Diazol-2-yl)-5-(trifluoromethyl)phenyl)acetamide

Step 1: 3-Nitro-5-(trifluoromethyl)benzoic acid methyl ester

H ₂ SO ₄ (12 mL, 225 mmol) was added dropwise to a mixture of 3-nitro-5-(trifluoromethyl)benzoic acid (20 g, The mixture was stirred for 16 h. The solvent was then concentrated, and the use of NaHCO ₃ solution was adjusted to pH = 9. The solvent was concentrated and the residue was purified eluting with EtOAc EtOAc EtOAc 20g, 76mmol, 90% yield): ¹ H NMR (400MHz, CD ₃ OD) δ 8.99 (s, 1H), 8.74 (s, 1H), 8.62 (s, 1H), 4.01 (s, 3H); - LCMS m/z 250 (M + 1).

Step 2: 3-Nitro-5-(trifluoromethyl)benzamide

A mixture of 3-nitro-5-(trifluoromethyl)benzoic acid methyl ester (20 g, 80 mmol) eluted with EtOAc (EtOAc m. The solvent was then concentrated to give an off-white solid of 3-nitro-5- (trifluoromethyl) benzoyl hydrazine (20g, 72.2mmol, 90% ^{yield): 1 H NMR (400MHz,} CD 3 OD) δ 8.89 ( s, 1H), 8.65 (s, 1H), 8.50 (s, 1H); ES-LCMS m/z 250 (M+H).

Step 3: 2-Methyl-5-(3-nitro-5-(trifluoromethyl)phenyl)-1,3,4- Diazole

A mixture of 1,1,1-triethoxyethane (156 g, 963 mmol) containing 3-nitro-5-(trifluoromethyl)benzhydrazide (20 g, 80 mmol) was taken. The solvent is then concentrated to give 2-methyl-5-(3-nitro-5-(trifluoromethyl)phenyl)-1,3,4- as a black solid. Diazole (20 g, 65.9 mmol, 82% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 9.04 (s, 1H), 8.71 (s, 1H), 8.66 (s, 1H), 2.67 (s, 1H); ES-LCMS m/z 274 (M+H).

Step 4: 2-Methyl-5-(3-nitro-5-(trifluoromethyl)phenyl)-1,3,4- Diazole

Take 2-methyl-5-(3-nitro-5-(trifluoromethyl)phenyl)-1,3,4- Oxadiazole (20g, 73.2mmol) and Pd / C (0.779g, 7.32mmol) of MeOH (25mL) The mixture was stirred under 35psi of H ₂ gas and the mask 25 ℃ 12h. The mixture was then filtered and the filtrate was concentrated and crystallised eluted with EtOAc (15 <RTI ID=0.0> Dioxazol-2-yl)-5-(trifluoromethyl)aniline (17 g, 66.4 mmol, 91% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.46 (s, 1H), 7.42 (s , 1H), 7.07 (s, 1H), 2.61 (s, 3H); ES-LCMS m/z 244 (M+H).

Step 5: 2- (4- (4-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (3- ( 5-methyl-1,3,4- Diazol-2-yl)-5-(trifluoromethyl)phenyl)acetamide

2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (300 mg) at 25 ° C , 0.729mmol), 3-(5-methyl-1,3,4- Oxadiazol-2-yl) -5- (trifluoromethyl) aniline (195mg, 0.802mmol), and Et ₃ N (0.203ml, 1.458mmol) of DCM (15ml) was added a mixture of HATU (333mg, 0.875mmol) . The mixture was then stirred for 2 h, the mixture was concentrated and residue was purified eluting with DCM (30 <RTIgt; The organic extract was washed with brine (20 mL) dried over sodium sulfate. The crude product was purified by preparative TLC (DMeOH:MeOH = 30:1, _Rf = 0.7) to yield 2-(4-(4-ethoxy-6-((4-methoxybenzyl)) pyridin-3-yl) -2-fluorophenyl) - N - (3- (5- methyl-1,3,4 Dioxazol-2-yl)-5-(trifluoromethyl)phenyl)acetamide (60 mg, 0.094 mmol, 13% yield): ¹ H NMR (400 MHz,MeOD- d 4) δ 8.52 (br. s., 1H), 7.99 (br.s., 1H), 7.95 (br.s., 1H), 7.42-7.39 (m, 2H), 7.30 (d, J = 8.4 Hz, 3H), 6.89 (d , J = 8.6 Hz, 3H), 6.52-6.50 (m, 1H), 5.11 (br.s., 2H), 4.64 - 4.62 (m, 2H), 4.31 (d, J = 7.1 Hz, 2H), 2.63 (br.s., 3H), 1.38 (t, J = 7.1 Hz, 3H); ES-LCMS m/z 637 (M+H).

Step 6: 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (5- methyl Base-1,3,4- Diazol-2-yl)-5-(trifluoromethyl)phenyl)acetamide

A mixture of 2- (4- (4-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (3- (5 -methyl-1,3,4- Oxadiazol-2-yl) -5- (trifluoromethyl) phenyl) acetyl amine (60mg, 0.094mmol) and Pd / C (10.03mg, 0.094mmol) of MeOH (15mL) in a mixture of H ₂ gas mask Stir at 0.5 ° C for 0.5 h. The mixture is then filtered, the filtrate is concentrated and the residue obtained is purified by preparative HPLC to yield 2-(4-(4-ethoxy-6-s-oxyl-1,6-dihydropyridin-3-yl)-2 -fluorophenyl)- N -(3-(5-methyl-1,3,4- Diazol-2-yl)-5-(trifluoromethyl)phenyl)acetamide (41.53 mg, 0.079 mmol, 84% yield): ¹ H NMR (400 MHz, DMSO- d 6) δ 11.40- 11.29 (m, 1H), 10.86 (s, 1H), 8.50 (s, 1H), 8.21 (s, 1H), 7.86 (s, 1H), 7.40-7.29 (m, 2H), 7.23 (d, J = 2.6 Hz, 2H), 5.78 (s, 1H), 4.02 (q, J = 7.1 Hz, 2H), 3.79 (s, 2H), 2.58 (s, 3H), 1.26 (t, J = 6.9 Hz, 3H) ;ES-LCMS m/z 517 (M+H).

Example 30: 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (5- (1,1 , 1-trifluoro-2-methylpropan-2-yl) Zin-3-yl)acetamide

Step 1: 5,5,5-Trifluoro-4,4-dimethyl-3-oxo-valeronitrile

N- BuLi (106 mL, 264 mmol) was added to a mixture of EtOAc &lt;RTI ID=0.0&gt; The mixture was stirred at -30 ° C for 0.5 h. Then, 3,3,3-trifluoro-2,2-dimethylpropionic acid methyl ester (30 g, 176 mmol) was added dropwise to the mixture. The mixture was stirred at 25 ° C for 10 h. A mixture of aqueous solution of NH ₄ Cl (50mL) quenched, (300mL x 3) extracted with EA. The organic layer was dried over sodium sulfate, filtered and concentrated to afford 5,5,5-trifluoro-4,4-dimethyl-3-oxoxypenteronitrile (22 g, 122.9 mmol, 70 % yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.75 (s, 2H), 1.41 (s, 6H).

Step 2: 5-(1,1,1-Trifluoro-2-methylpropan-2-yl) Zyrazin-3-amine

After cooling to a solution of hydroxylamine hydrochloride 0 ℃ of (23.2g, 336mmol) water (300 mL) was added a mixture of NaHCO ₃ (30g, 351mmol) and adjusted to pH = 7.5. A solution of 5,5,5-trifluoro-4,4-dimethyl-3-oxovaleronitrile (30 g, 167.4 mmol) in MeOH (40 mL) was then added. The mixture was stirred at 65 ° C for 15 h. After cooling, the mixture was acidified to pH = 1 using concentrated HCl then refluxed for 2 h. After cooling to room temperature, the mixture was neutralized to pH = 8 using 4M NaOH. The mixture was extracted using EA (300 mL x 2). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by vermiculite column chromatography (PE/EA = 8:1 to 3:1). All the fractions containing the product (PE/EA = 2:1, R _f = 0.6) were judged by TLC to be combined and concentrated to give 5-(1,1,1-trifluoro-2-methylpropane) as a red solid. 2-base) Oxazol-3-amine (19.5 g, 100.5 mmol, 60% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.79 (s, 1H), 3.96 (s., 2H), 1.53 (s, 6H); ES-LCMS m/z : 195 (M+H).

Step 3: 2- (4- (4-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (5- ( 1,1,1-trifluoro-2-methylpropan-2-yl) Zin-3-yl)acetamide

In the presence of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (55.1 g, 134 mmol) 5-(1,1,1-trifluoro-2-methylpropan-2-yl)iso Oxadiazol-3-amine (26g, 134mmol) of pyridine (500 mL) was added dropwise ^{_{T 3 P ® (137.5mL, 134mmol}} ), and stirred at 25 ℃ 1h. TLC analysis indicated that after the starting material had been completely consumed, the mixture was poured into cold water (1 L) with stirring. After the mixture was stirred for 0.5 h, it was allowed to stand for 10 h. The solid was filtered, using H ₂ O (200mL x 3) and TBME (200mL x 2), dried and vacuum dried to yield an off-white solid of 2- (4- (4-ethoxy-6 - ((4-methoxy benzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (5- (1,1,1- trifluoro-2-methylpropan-2-yl) iso Zyridin-3-yl)acetamide (65 g, 100 mmol, 74% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.94 (s, 1H), 7.40-7.32 (m, 3H), 7.26 (d) , J = 9.6 Hz, 2H), 6.90 (d, J = 8.8 Hz, 3H), 6.43 (s, 1H), 5.26 (s, 2H), 4.11 (q, J = 7.2 Hz, 2H), 3.81 (s , 2H), 3.78 (s, 3H), 1.56 (s, 6H), 1.35 (t, J = 7.2 Hz, 3H); ES-LCMS m/z : 588 (M+H).

Step 4: 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (5- (1,1 , 1-trifluoro-2-methylpropan-2-yl) Zin-3-yl)acetamide

Containing 2- (4- (4-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (5- (1 , 1,1-trifluoro-2-methylpropan-2-yl) To a suspension of DCM (1 L) of oxazol-3-yl)acetamide (100 g, 170 mmol), EtOAc (EtOAc) The mixture was stirred at 25 ° C for 2 h. The mixture was then concentrated. After dropping the residue in H ₂ O (500mL), saturated Na ₂ CO ₃ solution and adjusted to pH = 7.5. The precipitate was filtered, using H ₂ O (350mL x 3) and dried in vacuo. PE/EA (3:1, v / v , 300 mL) was added to the solid and stirred for 0.5 h. The solid was filtered and washed with PE/EA (3:1, v / v , 100 mL x 2). The solid was redissolved in DCM / MeOH (20:1, v / v , 1.5L). The solid was filtered, using CH ₃ CN (50mL x 2) washed, and dried in vacuo. The residual solid was added to EtOH (2.5 L) and heated to 80 °C. After the solid was completely dissolved, the mixture was concentrated in vacuo to give 2-(4-(4-ethoxy-6-s-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl as a white solid. - N -(5-(1,1,1-trifluoro-2-methylpropan-2-yl)iso Zyridin-3-yl)acetamide (61.4 g, 131 mmol, 77% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.40-7.30 (m, 2H), 7.25-7.18 (m, 2H), 6.88 (s, 1H), 5.98 (s, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.81 (s, 2H), 1.56 (s, 6H), 1.37 (t, J = 7.2 Hz, 3H) ); ES-LCMS m / z : 468 (m + H).

Example 31: 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (6- (1- hydroxy -2-methylpropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide

Step 1: 5-Nitro-3-(trifluoromethyl)pyridin-2-ol

Containing 3- (trifluoromethyl) pyridin-2-ol (10g, 61.3mmol) of _{H 2 SO 4 (50mL, 938mmol} ) was added dropwise a solution of nitric acid (3.01ml, 67.4mmol). After 30 minutes, the ice bath was left and the reaction was stirred at 25 ° C for 72 h. The reaction mixture was added to ice. The resulting precipitate was collected by filtration, rinsed using H ₂ O, and air-dried to produce a first crop. The mother liquor was evaporated to less than 100 mL to give another batch of product which was cooled on an ice bath and adjusted to pH 8 with NaOH. The mixture was extracted with EA (100 mL). The organic layer was dehydrated and concentrated to give a product which was combined with the first crop to give 5-nitro-3-(trifluoromethyl)pyridin-2-ol (9 g, 39.9 mmol, 65% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.84 (d, J = 2.8 Hz, 1H), 8.56 (d, J = 2.8 Hz, 1H); ES-LCMS m/z : 209.0 (M+H).

Step 2: 2-Chloro-5-nitro-3-(trifluoromethyl)pyridine

In a solution of 5-nitro-3- (trifluoromethyl) pyridin-2-ol (9g, 43.2mmol) was added SOCl the amount of catalyst _{DMF (0.033ml, 0.432mmol) 2 (} 30mL, 411mmol). The mixture was stirred at 80 ° C overnight. LCMS analysis indicated the solvent was removed in vacuo after the starting material had been consumed. The residue was dissolved in H ₂ O and extracted using EA. The organic layer was washed with aqueous NaHCO ₃ and brine. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated and the crude product was purified eluting EtOAc EtOAc EtOAc , 34.7mmol, 80% yield): ¹ H NMR (400MHz, CD ₃ OD) δ 9.43 (d, J = 2.8 Hz, 1H), 8.92 (d, J = 2.4 Hz, 1H); ES-LCMS m /z: 225.2 (M+H).

Step 3: 2-Cyano-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetic acid tert-butyl ester

Add 2-cyano group to a solution of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (5 g, 22.07 mmol) and K ₂ CO ₃ (6.10 g, 44.1 mmol) in THF (150 mL) Tert-butyl acetate (3.74 g, 26.5 mmol). The resulting mixture was stirred at 70 ° C overnight with nitrogen. After TLC analysis (PE/EA = 10/1) showed that the starting material had been consumed, solvent was evaporated in vacuo. The residue was dissolved in EA (100mL), washed with H ₂ O (50mL) and brine (50mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give crystals of &lt;RTI ID=0.0&gt; 21.13 mmol, 96% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 9.08 (s, 1H), 8.59 (br.s., 1H), 4.63 (br.s., 1H), 1.55 (s , 9H); ES-LCMS m/z: 332.1 (M+H).

Step 4: 2-(5-Nitro-3-(trifluoromethyl)pyridin-2-yl)acetonitrile

Add HCl to a solution of tert-butyl 2-cyano-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetate (7 g, 21.13 mmol) in MeOH (100 mL) Aqueous solution (40 mL, 1316 mmol). The resulting mixture was stirred at 100 ° C overnight. After TLC analysis (PE/EA = 10/1) showed that the starting material had been consumed, solvent was evaporated in vacuo. The residue was dissolved in H ₂ O (50mL), using EA (100mL) and extracted. The organic layer was washed with aq. NaHCO ₃ and brine and dried over sodium sulfate. After filtration, the filtrate was concentrated and purified to purified crystals eluted elute elute Acetonitrile (4.3 g, 17.77 mmol, 84% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 9.59 (s, 1H), 8.88 (d, J = 2.4 Hz, 1H), 4.86 (s, 2H); ES-LCMS m/z: 2321. (M+H).

Step 5: 2-Methyl-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanenitrile

In a solution of 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetonitrile (1 g, 4.33 mmol) and Cs ₂ CO ₃ (4.23 g, 12.98 mmol) in MeCN (30 mL) Methyl iodide (3.07 g, 21.63 mmol) was added. The resulting mixture was stirred at 40 ° C overnight in an autoclave. LCMS analysis indicated the solvent was removed in vacuo after the starting material had been consumed. The residue was dissolved in EA (100mL), washed with H ₂ O (50mL) and brine (50mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column EtOAc (EtOAc/EtOAc (EtOAc) Propionitrile (0.7 g, 2.70 mmol, 62% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 9.56 (s, 1H), 8.93 (d, J = 2.8 Hz, 1H), 1.90 (s, 6H); ES-LCMS m/z: 260.1 (M+H).

Step 6: 2-Methyl-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanal

In a solution of 2-methyl-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanenitrile (700 mg, 2.70 mmol) in DCM (30 mL) DIBAL-H (5.40 mL, 5.40 mmol) was added. The resulting mixture was stirred at -50 °C for 1 h and slowly warmed to room temperature. After LCMS analysis indicated the starting material is consumed, a mixture quenched with saturated NH ₄ Cl. The mixture was dissolved in water and extracted with EA. The organic layer is dehydrated and concentrated, and the crude product is purified by column chromatography to yield 2-methyl-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl) as a yellow oil. Propionaldehyde (200 mg, 0.763 mmol, 28% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 9.67 (s, 1H), 9.54 (s, 1H), 8.89 (s, 1H), 1.56 (s, 6H); ES-LCMS m/z: 263.1 (M+H).

Step 7: 2-(5-Amino-3-(trifluoromethyl)pyridin-2-yl)-2-methylpropan-1-ol

Take 2-methyl-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanal (100 mg, 0.381 mmol) with hydrazine nickel (22.39 mg, 0.381 mmol) in MeOH (30 mL) The solution was stirred at 25 ° C under hydrogen atmosphere overnight. After TLC analysis (PE/EA = 5/1) showed that the starting material had been consumed, the mixture was filtered. The filtrate was concentrated to give 2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)-2-methylpropan-1-ol (60 mg, 0.256 mmol, 67% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.08 (br.s., 1H), 7.36 (d, J = 2.8 Hz, 1H), 1.31 (s, 6H); ES-LCMS m/z: 235.1 (M+H ).

Step 8: 2- (4- (4-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (6- ( 1-hydroxy-2-methylpropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide

Taking 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (50 mg, 0.122 mmol), 2-(5-Amino-3-(trifluoromethyl)pyridin-2-yl)-2-methylpropan-1-ol (28.5 mg, 0.122 mmol), HATU (92 mg, 0.243 mmol) and DIEA ( A solution of 0.064 mL, 0.365 mmol of DCM (10 mL) was stirred at 25 °. LCMS analysis showed the starting material had been consumed, ₂ O the mixture was washed with H using. The organic layer was washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated and the crude product was purified by preparative TLC (DCM /MeOH = 20/1) to give 2-(4-(4-ethoxy-6-((4-methoxybenzyl)) pyridin-3-yl) -2-fluorophenyl) - N - (6- (1- hydroxy-2-methylpropan-2-yl) -5- (trifluoromethyl) pyridin-3-yl) acetate Indoleamine (20 mg, 0.032 mmol, 26% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.95 (br.s., 1H), 8.50 (s, 1H), 7.99 (s, 1H), 7.43 -7.39 (m, 3H), 7.30-7.24 (m, 2H), 6.95-6.91 (m, 2H), 6.48 (s, 1H), 5.30 (s, 2H), 4.16-4.11 (m, 2H), 3.87 - 3.79 (m, 6H), 1.40-1.38 (m, 9H); ES-LCMS m/z: 628.3 (M+H).

Step 9: 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (6- (1- hydroxy -2-methylpropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide

A mixture of 2- (4- (4-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (6- (1 - Hydroxy-2-methylpropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide (20 mg, 0.032 mmol) in EtOAc (EtOAc m. Stir at °C. LCMS analysis indicated that after the starting material had been consumed, solvent was removed in vacuo and crude product was purified by preparative HPLC (under neutral conditions) to yield 2-(4-(4- ethoxy-6- oxy-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (6- (1- hydroxy-2-methylpropan-2-yl) -5- (trifluoromethyl Benzyl-3-yl)acetamide (8.8 mg, 0.017 mmol, 54% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.91 (s, 1H), 8.46 (d, J = 2.0 Hz , 1H), 7.40-7.35 (m, 2H), 7.24-7.21 (m, 2H), 5.98 (s, 1H), 4.13-4.08 (m, 2H), 3.82 (s, 4H), 1.37 (t, J = 7.0 Hz, 9H); ES-LCMS m/z: 508.2 (M+H).

Example 32: 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -3-fluorophenyl) - N - (4- (3- hydroxy -2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

Step 1: 4-Ethoxypyridine 1-oxide

Sodium ethoxide (40.8 g, 600 mmol) was added to a mixture of 4-nitropyridine 1-oxide (28 g, 200 mmol) in THF (50 mL). The mixture was stirred at 25 ° C for 16 h. The reaction residue was then concentrated and the crude material was purified eluting with EtOAc EtOAc EtOAc All the fractions containing the product (DCM/MeOH = 25:1, R _f = 0.6) were judged by TLC to be combined and concentrated to give 4-ethoxypyridine 1-oxide (20 g, 101 mmol, 50%) Yield). ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 8.20 (d, J = 7.6 Hz, 2H), 7.12 (d, J = 7.6 Hz, 2H), 4.18 (q, J = 7.2 Hz, 2H), 1.42 ( t, J = 6.8 Hz, 3H); ES-LCMS m/z : 140.0 (M+H).

Step 2: 4-Ethoxypyridin-2-ol

A mixture of 4-ethoxy-pyridine-1-oxide (20g, 144mmol) of Ac ₂ O (200mL, 7.836mol) was heated to reflux for 4h. The solvent was then removed in vacuo and the residue was crystallisjjjjjjjjjjjj The mixture was then concentrated and the crude was purified by EtOAc EtOAc (EtOAc:EtOAc All the fractions containing the product (DCM/MeOH = 10:1, R _f = 0.6), which were judged by TLC, were combined and concentrated to give 4-ethoxypyridin-2-ol (17 g, 104 mmol, 72%) Yield). ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 8.20 (d, J = 7.6 Hz, 2H), 7.12 (d, J = 7.6 Hz, 2H), 4.18 (q, J = 7.2 Hz, 2H), 1.42 ( t, J = 6.8 Hz, 3H); ES-LCMS m/z : 140.0 (M+H).

Step 3: 4-Ethoxy-5-iodopyridin-2-ol

To a mixture of 4-ethoxypyridin-2-ol (17 g, 122 mmol) in DMF (125 mL). The mixture was stirred at 80 ° C for 16 h. The mixture was concentrated and purified by preparative EtOAc (EtOAc/EtOAc (EtOAc) . TLC (DCM / MeOH = 10:1, _Rf = 0.6): ¹ H NMR (400 MHz, MeOH - d ₄ ) δ 7.70 (s, 1H), 5.91 (s, 1H), 4.10 (q, J = 7.2 Hz , 2H), 1.44 (t, J = 6.8 Hz, 3H); ES-LCMS m/z : 265.9 (M+H).

Step 4: 2-(Benzyloxy)-4-ethoxy-5-iodopyridine

Add (bromomethyl)benzene (2.87 g, 16.75 mmol) and silver carbonate (7.70 g) to a mixture of 4-ethoxy-5-iodopyridin-2-ol (3.7 g, 13.96 mmol) in THF (10 mL). , 27.9mmol). The mixture was stirred at 70 ° C for 16 h. The reaction residue was then filtered and the filtrate was concentrated. The mixture was diluted with water (30 mL) and extracted with DCM (30 mL The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by column chromatography (PE/EA = 5:1). All the fractions containing the product (PE/EA = 5:1, _Rf = 0.6) were judged by TLC to be combined and concentrated to give 2-(phenylmethyloxy)-4-ethoxy- 5-iodopyridine (4.2 g, 10.64 mmol, 76% yield). ^{1 H NMR (400MHz, MeOH- d} 4) δ 8.25 (s, 1H), 7.47-7.41 (m, 2H), 7.40-7.30 (m, 3H), 6.41 (s, 1H), 5.32 (s, 2H) , 4.16 (q, J = 7.2 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H); ES-LCMS m/z 356.0 (M+H).

Step 5: 2-(4-Bromo-3-fluorophenyl)acetic acid methyl ester

(50mL) was added a mixture of SOCl ₂ (1.879mL, 25.7mmol) and DMF (0.166mL, 2.146mmol) in MeOH containing 2- (4-bromo-3-fluorophenyl) acetic acid (5g, 21.46mmol) of. The mixture was then stirred at 80 ° C for 16 h. The mixture was concentrated, extracted with EtOAc ₍ EtOAc EtOAc) The combined organic extracts were washed with EtOAcq EtOAc (EtOAc m. Yield: ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.53 (t, J = 7.6 Hz, 1H), 7.15 (dd, J = 1.6, 9.6 Hz, 1H), 7.04-6.99 (m, 1H) , 3.67 (s, 3H), 3.65 (s, 2H); ES-LCMS m/z 249.0 (M+H+2).

Step 6: 2-(3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid methyl ester

In the presence of 2-(4-bromo-3-fluorophenyl)acetic acid methyl ester (5 g, 20.24 mmol) of 1,4-two Add 4,4,4',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolan) to a mixture of alkane (10 mL) Alkane) (5.65 g, 22.26 mmol), KOAc (3.97 g, 40.5 mmol) and PdCl ₂ (dppf) (1.481 g, 2.024 mmol). The resulting suspension was stirred at 110 ° C under nitrogen atmosphere for 16 h. The mixture was then filtered and concentrated. The crude product was purified by column chromatography (PE/EA = 5:1). All the fractions containing the product (PE/EA = 5:1, _Rf = 0.6) were judged by TLC to be combined and concentrated to give 2-(3-fluoro-4-(4,4,5) as a yellow oil. 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid methyl ester (6 g, 16.32 mmol, 81% yield): ¹ H NMR (400 MHz, MeOH - d ₄ ) δ 7.66-7.58 (m, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 10.4 Hz, 1H), 3.67 (s, 5H), 1.33 (s, 12H) ); ES-LCMS m/z 295.1 (M+H).

Step 7: 2-(3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid

Containing methyl 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate ( LiOH‧H ₂ O (3.57 g, 85 mmol) was added to a mixture of THF (30 mL) and water (30 mL). The mixture was stirred at 25 ° C for 16 h. The reaction residue was then concentrated, diluted with EA (200 mL) and EtOAc. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by column chromatography (PE/EA = 2:1). All the fractions containing the product (PE/EA = 2:1, R _f = 0.6) were judged by TLC to be combined and concentrated to give 2-(3-fluoro-4-(4,4,5) as a pale yellow oil. ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid (5 g, 14.28 mmol, 84% yield): ¹ H NMR (400 MHz, CD ₃ OD ) δ 7.66 (t, J = 6.8Hz, 1H), 7.12 (d, J = 7.6Hz, 1H), 7.03 (d, J = 10.0Hz, 1H), 3.66 (s, 2H), 1.37 (s, 12H ); ES-LCMS m/z 281.1 (M+H).

Step 8: Ethyl 2,2-dimethyl-3-(2-(trifluoromethyl)phenyl)propanoate

n- BuLi (24.60 mL, 61.5 mmol) was added dropwise to a mixture of diisopropylamine ( 8.00 mL, 57.1 mmol) in THF (300 mL). The mixture was stirred at 0 ° C for 1 h. The mixture was then cooled to -30 ° C and a solution of ethyl isobutyrate (6.12 g, 52.7 mmol) in THF (2 mL). The mixture was stirred at -30 ° C for 1 h. To the mixture was added a solution of 1-(bromomethyl)-2-(trifluoromethyl)benzene (10.5 g, 43.9 mmol) in THF (5 mL). The whole mixture was stirred at -30 ° C for 3 h and then stirred at 25 ° C for 12 h. Aqueous NH ₄ Cl mixture quenched, extracted with EA. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by column chromatography (PE/EA = 200:1). All the fractions containing the product (PE/EA = 10:1, R _f = 0.6) were judged by TLC to be combined and concentrated to give a pale yellow solid of 2,2-dimethyl-3-(2-(trifluoro) Ethyl phenyl)propionic acid ethyl ester (10 g, 35.3 mmol, 80% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.62 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.14 (s, 3H), 1.25 (t, J = 7.2Hz, 3H), 1.18 (s, 6H); ES-LCMS m / z 275 (m + H).

Step 9: 2,2-Dimethyl-3-(4-nitro-2-(trifluoromethyl)phenyl)propanoic acid ethyl ester

After cooling to 0 ℃ containing the 2,2-dimethyl-3- (2- (trifluoromethyl) phenyl) propanoic acid ethyl ester (10g, 36.5mmol) of _{H 2 SO 4 (5mL, 94mmol} ) Potassium nitroperoxylate (4.05 g, 40.1 mmol) was added portionwise over the solution. The mixture was stirred at 0 ° C for 30 min. The mixture was poured onto ice-water and extracted with DCM (100 mL x 2). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to yield of 2,2-dimethyl-3-(4-nitro-2-(trifluoromethyl)phenyl)propanoic acid Base ester (8.5 g, 24.54 mmol, 67% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.59 (d, J = 2.4 Hz, 1H), 8.47 (dd, J = 2.4, 8.8 Hz, 1H ), 7.82 (d, J = 8.4 Hz, 1H), 5.97-5.83 (m, 2H); ES-LCMS m/z 320 (M+H).

Step 10: 3-(4-Amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoic acid ethyl ester

Ethyl 2,2-dimethyl-3-(4-nitro-2-(trifluoromethyl)phenyl)propanoate (8.5 g, 26.6 mmol) and Pd/C (0.283 g, 2.66) The reaction mixture of MeOH (50 mL) was hydrogenated using an H-tube apparatus (conditions: 50 ° C, 50 psi, 24h). The mixture was filtered and the filtrate was concentrated. The crude product was purified by column chromatography (PE/EA = 10:1). All fractions containing the product (PE/EA = 5:1, _Rf = 0.4) were judged by TLC to be combined and concentrated to give 3-(4-amino-2-(trifluoromethyl)phenyl. ) -2,2-dimethyl-propionic acid ethyl ester (7g, 22.42mmol, 84% ^{yield): 1 H NMR (400MHz,} CDCl 3) δ 6.98 (d, J = 8.4Hz, 1H), 6.91 ( d, J = 2.4 Hz, 1H), 6.71 (dd, J = 2.4, 8.4 Hz, 1H), 4.15 (q, J = 6.8 Hz, 2H), 3.00 (s, 2H), 1.25 (t, J = 7.2) Hz, 3H), 1.14 (s, 6H); ES-LCMS m/z 290 (M+H).

Step 11: 3-(4-Amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropan-1-ol

Add in portions in a mixture of THF (200 mL) containing ethyl 3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (2 g, 6.91 mmol) LAH (0.525 g, 13.83 mmol). The mixture was stirred at 25 ° C for 10 h. The mixture was quenched with 15% aqueous NaOH (10 mL). The mixture was dehydrated over sodium sulfate, filtered and concentrated. The residue was purified by vermiculite column chromatography (PE/EA = 8:1). All the fractions containing the product (PE/EA = 2:1, _Rf = 0.35) were determined by TLC to be combined and concentrated to give 3-(4-amino-2-(trifluoromethyl) as a pale yellow oil. Phenyl)-2,2-dimethylpropan-1-ol (1.1 g, 4.45 mmol, 64% yield): ¹ H NMR (400 MHz, CD ₃ Cl) δ: 7.17 (d, J = 8.4 Hz , 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.84 (dd, J = 2.4, 8.0 Hz, 1H), 3.31 (s, 2H), 2.67 (d, J = 1.2 Hz, 2H), 0.84 (s, 6H); ES-LCMS m/z 248 (M+H).

Step 12: 4-(3-((Tertiary butyldimethylmethyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl) aniline

Addition of imidazole to a mixture of 3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropan-1-ol (300 mg, 1.213 mmol) in DCM (150 mL) 124 mg, 1.820 mmol) and TBSCl (219 mg, 1.456 mmol). The mixture was then stirred at 25 ° C for 5 h. The mixture was filtered and the filtrate was concentrated. The crude product was purified by preparative TLC (PE / EA = 2: 1, R f = 0.5) yielded the pale yellow solid of 4- (3 - ((tert-butyl-dimethyl-Si-alkyl) oxy) -2,2 - dimethylpropyl)-3-(trifluoromethyl)aniline (350 mg, 0.930 mmol, 77% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.14 (d, J = 8.4 Hz, 1H ), 6.86 (d, J = 2.8 Hz, 1H), 6.70 (dd, J = 2.8, 8.4 Hz, 1H), 3.20 (s, 2H), 2.62 (d, J = 1.2 Hz, 2H), 0.87 (s) , 9H), 0.73 (s, 6H), 0.00 (s, 6H); ES-LCMS m/z 362 (M+H).

Step 13: N -(4-(3-((Tertiary dimethyl dimethyl decyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)-2 -(3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide

In the presence of 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid (5 g, 17.85 Add 4-(3-((t-butyldimethyl decyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)aniline to a solution of mmol) in DCM (100 mL) (7.10 g, 19.64 mmol), DIEA (6.24 mL, 35.7 mmol) and HATU (8.14 g, 21.42 mmol). The solution was stirred at 25 ° C for 16 h. The reaction mixture was then concentrated and the crude product was purified (EtOAc/EtOAc) All the fractions containing the product (PE/EA = 8:1, R _f = 0.6) were judged by TLC to be combined and concentrated to give N- (4-(3-(tert-butyldimethyl decane) as a white solid. Oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)-2-(3-fluoro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)acetamide (10 g, 12.83 mmol, 72% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.83 (d , J = 2.0 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 6.99 (dd, J = 4.8, 10.0 Hz, 2H), 3.63 (s, 2H), 3.26 (s, 2H), 2.69 (s, 2H), 1.11 (s, 12H), 0.86 (s, 9H), 0.73 (s, 6H), 0.00 (s, 6H); ES-LCMS m/z 624.2 (M+H).

Step 14: 2- (4- (6- (benzyl oxy) -4-ethoxy-pyridin-3-yl) -3-fluorophenyl) - N - (4- (3 - (( t-butoxide Dimethyl decyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

In the presence of 2-(benzyloxy)-4-ethoxy-5-iodopyridine (3.2 g, 9.01 mmol) of 1,4-two Add N- (4-(3-((t-butyldimethyl)alkyl)oxy)-2,2-dimethylpropyl)-3-(3) to a mixture of alkane (60 mL) and water (20 mL) Fluoromethyl)phenyl)-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl ) as acetamide _{(6.18g, 9.91mmol), Cs 2} CO 3 (5.87g, 18.02mmol) and _{PdCl 2 (dppf) (0.659g,} 0.901mmol). The mixture was stirred at 110 ° C for 16 h under nitrogen atmosphere. The reaction residue was then filtered, and the filtrate was concentrated, and the crude product was purified by silica gel column chromatography (PE/EA = 5:1). All the fractions containing the product (PE/EA = 5:1, R _f = 0.6) were judged by TLC to be combined and concentrated to give 2-(4-(6-(phenylmethyloxy)) as a pale yellow oil. 4-ethoxy-pyridin-3-yl) -3-fluorophenyl) - N - (4- (3 - (( tert-butyl-dimethyl-Si-alkyl) oxy) -2,2- Benzyl-3-(trifluoromethyl)phenyl)acetamide (4.2 g, 5.21 mmol, 58% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.96 (d, J = 2.0 Hz, 1H), 7.88 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 6.0 Hz, 3H), 7.42-7.36 (m, 2H), 7.36-7.30 (m, 2H) ), 7.27-7.17 (m, 2H), 6.50 (s, 1H), 5.38 (s, 2H), 4.16-4.12 (m, 2H), 3.77 (s, 2H), 3.36 (s, 2H), 2.81 ( s, 2H), 1.32 (t, J = 6.8 Hz, 3H), 0.97 (s, 9H), 0.85 (s, 6H), 0.12 (s, 6H); ES-LCMS m/z 725.2 (M+H) .

Step 15: 2- (4- (6- (benzyl oxy) -4-ethoxy-pyridin-3-yl) -3-fluorophenyl) - N - (4- (3- hydroxy-2,2 - Dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

Containing 2- (4- (6- (benzyl oxy) -4-ethoxy-pyridin-3-yl) -3-fluorophenyl) - N - (4- (3 - (( tert-butyl Adding TFA to a mixture of dimethyl decyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (4.5 g, 4.83 mmol) in DCM (30 mL) (4.46 mL, 57.9 mmol). The mixture was stirred at 25 ° C for 2 h. The reaction mass is then concentrated to residue, were added to MeCN (50mL) using NH ₄ OH made alkaline, and concentrated. The crude product was purified by column chromatography (PE/EA = 1:1). All the fractions containing the product (PE/EA = 1:1, R _f = 0.6) were judged by TLC to be combined and concentrated to give a pale yellow solid of 2-(4-(6-(benzyloxy))-4- ethoxy-pyridin-3-yl) -3-fluorophenyl) - N - (4- (3- hydroxy-2,2-dimethylpropyl) -3- (trifluoromethyl) phenyl) acetate Indoleamine (4.2 g, 4.19 mmol, 87% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.97 (s, 1H), 7.78 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H ), 7.51-7.43 (m, 3H), 7.38 (t, J = 7.2 Hz, 2H), 7.35-7.29 (m, 2H), 7.26-7.16 (m, 2H), 6.50 (s, 1H), 5.38 ( s, 2H), 4.14 - 4.11 (m, 2H), 3.77 (s, 2H), 2.80 (s, 2H), 2.03 (s, 2H), 1.32 (t, J = 6.8 Hz, 3H), 0.86 (s) , 6H); ES-LCMS m/z 611.2 (M+H).

Step 16: 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -3-fluorophenyl) - N - (4- (3- hydroxy -2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide

Containing 2- (4- (6- (benzyl oxy) -4-ethoxy-pyridin-3-yl) -3-fluorophenyl) - N - (4- (3- hydroxy-2,2 Pd/C (10%, 420 mg) was added to a mixture of MeOH (50 mL) of dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (4.2 g, 6.88 mmol). The mixture was stirred at 25 ° C for 16 h under H ₂ atmosphere. The reaction residue was then filtered and concentrated. The crude product was purified by preparative HPLC (MeCN/H ₂ O as eluting solvent, acidic conditions) to yield 2-(4-(4-ethoxy-6-s-oxy-1,6-dihydropyridine) as a white solid. 3-yl) -3-fluorophenyl) - N - (4- (3- hydroxy-2,2-dimethylpropyl) -3- (trifluoromethyl) phenyl) acetyl amine (2000.18 Mg, 3.84 mmol, 61% yield). TLC (DCM / MeOH = 10: 1, R f = 0.6): 1 H NMR (400MHz, CD 3 OD) δ 7.94 (s, 1H), 7.77-7.68 (m, 2H), 7.42 (d, J = 8.8 Hz, 1H), 7.37-7.29 (m, 1H), 7.27-7.17 (m, 2H), 6.36 (s., 1H), 4.25-4.15 (m, 2H), 3.75 (s, 2H), 2.76 (s , 2H), 1.33 (t, J = 6.8 Hz, 3H), 0.82 (s, 6H); ES-LCMS m/z 521.2 (M+H).

Example 33: 2- ((4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl 4-) - N - (3- (trifluoromethanesulfonyloxy Phenyl)acetamide

Step 1: 2-(4-(4-Ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid

2-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl) stirred under nitrogen at 20 ° C A solution of acetic acid (0.5 g, 1.215 mmol) in MeOH (10 mL). The reaction mixture was reacted with H ₂ balloon at 20 ° C for 12 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give crude (2-(4- ethoxy-6- </RTI>&lt;RTIID=0.0&gt; 0.4 g, 1.373 mmol). TLC (DCM / MeOH = 10: 1, R f = 0.2): 1 H NMR (400MHz, DMSO- d 6) δ 7.32-7.15 (m, 4H), 5.78 (s, 1H), 4.01-4.00 (m, 2H), 3.59 (s, 2H), 1.26-1.23 (m, 3H); ES-LCMS m/z 292 (M+H).

Step 2: 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (trifluoromethanesulfonyloxy Phenyl)acetamide

2-(4-(4-Ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid (80 mg, 0.275 mmol), 3-( A solution of trifluoromethyl)aniline (44.3 mg, 0.275 mmol), EtOAc (EtOAc) (EtOAc) After LCMS analysis indicated that the starting material had disappeared, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM, washed with H ₂ O and brine. The organic layer was evaporated to dryness and the crude material was purified by preparative HPLC to yield the product 2-(4-(4- ethoxy-6- </RTI> 2-fluorophenyl) - N - (3- (trifluoromethyl) phenyl) acetyl amine (14.56mg, 0.032mmol, 12% yield) of a yellow solid. _{^{1 H NMR (400MHz, CD 3}} OD): δ 8.03 (br.s., 1H), 7.77 (d, J = 8.2Hz, 1H), 7.69 (s, 1H), 7.51 (t, J = 8.0Hz, 1H), 7.46-7.36 (m, 2H), 7.31-7.24 (m, 2H), 6.28 (s, 1H), 4.24 - 4.19 (m, 2H), 3.84 (s, 2H), 1.41 (t, J = 6.8 Hz, 3H); ES-LCMS: m/z 435.1 (M+H).

Example 34: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (4- methyl Base-1 H -pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide hydrochloride

Step 1: 4-Methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1 H -pyrazole

Add a full amount of 4-A in a solution of 1-fluoro-3-nitro-5-(trifluoromethyl)benzene (500 mg, 2.391 mmol) and K ₂ CO _{3 (} 496 mg, 3.59 mmol) in DMF (3 mL) Base-1 H -pyrazole (196 mg, 2.391 mmol). The mixture was then heated to 110 ° C with stirring under nitrogen atmosphere and reacted for 15 h. LCMS analysis showed the starting material had disappeared. The solvent was removed in vacuo. The residue was dissolved in DCM (60mL), washed with the use of H ₂ O (20mL) and brine (20mL). The organic layer was dried over sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography (PE/EA = 10/1 to 5/1) to yield the pure product 4-methyl-1-(3) -Nitro-5-(trifluoromethyl)phenyl)-1 H -pyrazole (500 mg, 1.678 mmol, 70.2% yield): ¹ H NMR (400 MHz, CD ₃ OD): δ 8.83 (s, 1H) ), 8.46 (s, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 7.64 (s, 1H), 2.18 (s, 3H). ES-LCMS: m/z 272.2 (M+H).

Step 2: 3-(4-Methyl-1 H -pyrazol-1-yl)-5-(trifluoromethyl)aniline

Add a full amount of Pd/ once in a solution of 4-methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1 H -pyrazole (560 mg, 2.065 mmol) in MeOH (10 mL) C (21.98 mg, 0.206 mmol). It was then stirred under H ₂ atmosphere for 12 h. LCMS analysis showed the starting material had disappeared. The suspension (Celite ^®) filler was filtered through Celite using MeOH (2mL) and washed filter cake. Take the combined filtrate concentrated to dryness, the crude product was purified by preparative TLC (PE / EA = 5/1 , R f = 0.25), pure product 3- (4-methyl -1 H - pyrazol -1 -yl)-5-(trifluoromethyl)aniline (280 mg, 1.158 mmol, 56.1% yield). ¹ H NMR (400 MHz, CD ₃ OD): δ 7.96 (s, 1H), 7.52 (s, 1H), 7.15 (s, 2H), 6.82 (s, 1H), 2.15 (s, 3H). ES-LCMS: m/z 242.1 (M+H).

Step 3: 2- (4- (5-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (3- ( 4-methyl-1 H -pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide

Containing 3-(4-methyl-1 H -pyrazol-1-yl)-5-(trifluoromethyl)aniline (160 mg, 0.663 mmol) with 2-(4-(5-ethoxy-6) T ₃ P ^® (2111 mg) was added in portions to a solution of ((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (274 mg, 0.663 mmol) in pyridine (8 mL) , 3.32mmol). The mixture was then stirred at 16 ° C for 1 h. LCMS analysis showed the starting material had disappeared. After 10 mL of water was added dropwise to the reaction solution, the mixture was filtered. The filter pad was washed with water (20 mL) and dried in vacuo to yield the pure product 2-(4-(5-ethoxy-6-((4-methoxybenzyl)))pyridin-3-yl)- 2-fluorophenyl) - N - (3- (4- methyl -1 H - pyrazol-1-yl) -5- (trifluoromethyl) phenyl) acetyl amine (200mg, 0.263mmol, 39.7 %Yield). ¹ H NMR (400 MHz, CD ₃ OD): δ 8.24 (s, 1H), 8.06 (s, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.78 (s, 1H), 7.74 (s, 1H) ), 7.57 (s, 1H), 7.48-7.42 (m, 3H), 7.40 (d, J = 9.0 Hz, 3H), 6.91 (d, J = 8.8 Hz, 2H), 5.37 (s, 2H), 4.18 - 4.13 (m, 2H), 3.86 (s, 2H), 3.79 (s, 3H), 2.16 (s, 3H), 1.43 (t, J = 7.0 Hz, 3H). ES-LCMS: m/z 635.1 (M+H).

Step 4: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (4- methyl Base-1 H -pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide hydrochloride

A mixture of 2- (4- (5-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (3- (4 -Methyl-1 H -pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamidamine (160 mg, 0.252 mmol) in EtOAc (8 mL, 10.38 mmol) . LCMS analysis showed the starting material had disappeared. The solvent was removed in vacuo. The crude product was then purified by preparative HPLC (instrument: DB/column: ASB C18 150*25 mm / mobile phase A: water + 0.1% HCl / mobile phase B: MeCN / flow rate: 25 mL / min / gradient profile Description: 53-83 (B%)), yielded the pure product 2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)- N - (3- (4- methyl -1 H - pyrazol-1-yl) -5- (trifluoromethyl) phenyl) acetyl amine hydrochloride (15.92mg, 0.029mmol, 11.46% yield ). ^{1 H NMR (400MHz, MeOD- d} 4): δ 8.22 (s, 1H), 8.05 (s, 1H), 7.87 (s, 1H), 7.74 (s, 1H), 7.57 (s, 1H), 7.49- 7.41 (m, 1H), 7.39-7.35 (m, 3H), 7.30 (d, J = 2.0 Hz, 1H), 4.16-4.12 (m, 2H), 3.84 (s, 2H), 2.16 (s, 3H) , 1.47 (t, J = 7.0 Hz, 3H). ES-LCMS: m/z 515.2 (M+H).

Example 35: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (3- methyl Base-1 H -pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide hydrochloride

Step 1: 3-Methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1 H -pyrazole

Add a full amount of 3-A in a solution of 1-fluoro-3-nitro-5-(trifluoromethyl)benzene (500 mg, 2.391 mmol) and K ₂ CO ₃ (496 mg, 3.59 mmol) in DMF (10 mL) Base-1 H -pyrazole (196 mg, 2.391 mmol). The mixture was then heated to 110 ° C with stirring under nitrogen atmosphere and reacted for 15 h. LCMS analysis showed the starting material had disappeared. The solvents were removed in vacuo, the resulting residue was dissolved in DCM (40mL), washed with the use of H ₂ O (15mL) and brine (15mL). The organic layer is dehydrated with sodium sulfate, filtered and concentrated, and the residue obtained is purified by column chromatography (PE/EA=8/1 to 3/1) to yield pure product 3-methyl-1-(3) -Nitro-5-(trifluoromethyl)phenyl)-1 H -pyrazole (300 mg, 1.007 mmol, 42.1% yield). _{^{1 H NMR (400MHz, CD 3}} OD): δ 8.84 (s, 1H), 8.47 (s, 1H), 8.41 (d, J = 2.4Hz, 1H), 8.35 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 2.36 (s, 3H). ES-LCMS: m/z 272.0 (M+H).

Step 2: 3-(3-Methyl-1 H -pyrazol-1-yl)-5-(trifluoromethyl)aniline

Add a full amount of Pd/ once in a solution of 3-methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1 H -pyrazole (300 mg, 1.106 mmol) in MeOH (10 mL) C (11.77 mg, 0.111 mmol). The mixture was then stirred under hydrogen atmosphere for 12 h. LCMS analysis showed the starting material had disappeared. The suspension (Celite ^®) filler was filtered through Celite using MeOH (2mL) and washed filter cake. Take the combined filtrate concentrated to dryness, the crude product was purified by preparative TLC (PE / EA = 5/1 , R f = 0.35), pure product 3- (3-methyl -1 H - pyrazol -1 -yl)-5-(trifluoromethyl)aniline (300 mg, 1.045 mmol, 94% yield). ¹ H NMR (400 MHz, CD ₃ OD): δ 8.05 (d, J = 2.4 Hz, 1H), 7.18-7.12 (m, 2H), 6.82 (s, 1H), 6.30 (d, J = 2.2 Hz, 1H) ), 2.32 (s, 3H). ES-LCMS: m/z 242.1 (M+H).

Step 3: 2- (4- (5-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (3- ( 3-methyl-1 H -pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide

Containing 3-(3-methyl-1 H -pyrazol-1-yl)-5-(trifluoromethyl)aniline (250 mg, 1.036 mmol) with 2-(4-(5-ethoxy-6) - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) pyridine (5mL) acetate (429mg, 1.036mmol) was added portionwise a solution of T ₃ P ^® (3298mg , 5.18mmol). The mixture was stirred at 16 ° C for 1 h. LCMS analysis showed the starting material had disappeared. After 10 mL of water was added dropwise to the reaction solution, the mixture was filtered. The filter pad was washed with water (20 mL) and dried in vacuo to yield the pure product 2-(4-(5-ethoxy-6-((4-methoxybenzyl)))pyridin-3-yl)- 2-fluorophenyl) - N - (3- (3- methyl -1 H - pyrazol-1-yl) -5- (trifluoromethyl) phenyl) acetyl amine (280mg, 0.357mmol, 34.5 %Yield). _{^{1 H NMR (400MHz, CD 3}} OD): δ 8.25 (s, 1H), 8.15 (d, J = 2.6Hz, 1H), 7.96 (d, J = 2.0Hz, 1H), 7.85 (s, 1H), 7.75 (s, 1H), 7.50-7.43 (m, 3H), 7.41 (d, J = 9.0 Hz, 3H), 6.92 (d, J = 8.8 Hz, 2H), 6.36 (d, J = 2.4 Hz, 1H) ), 5.37 (s, 2H), 4.18-4.13 (m, 2H), 3.86 (s, 2H), 3.79 (s, 3H), 2.34 (s, 3H), 1.43 (t, J = 7.0 Hz, 3H) . ES-LCMS: m/z 635.1 (M+H).

Step 4: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (3- methyl Base-1 H -pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide hydrochloride

A mixture of 2- (4- (5-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (3- (3 a solution of -methyl-1 H -pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide (220 mg, 0.347 mmol) in EtOAc (8 mL, 10.38 mmol) . LCMS analysis showed the starting material had disappeared. The solvent was removed in vacuo. The crude product was then purified by preparative HPLC (instrument: DB/column: ASB C18 150*25 mm / mobile phase A: water + 0.1% HCl / mobile phase B: MeCN / flow rate: 25 mL / min / gradient profile Description: 53-83 (B%)), yielded the pure product 2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)- N- (3-(3-Methyl-1 H -pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide hydrochloride (113 mg, 0.197 mmol, 56.8% yield) . ¹ H NMR (400 MHz, MeOD- d ₄ ): δ 8.24 (s, 1H), 8.15 (d, J = 2.2 Hz, 1H), 7.85 (s, 1H), 7.74 (s, 1H), 7.50-7.44 ( m, 2H), 7.43-7.37 (m, 3H), 6.36 (d, J = 2.2 Hz, 1H), 4.21-4.16 (m, 2H), 3.85 (s, 2H), 2.34 (s, 3H), 1.48 (t, J = 6.8 Hz, 3H). ES-LCMS: m/z 515.2 (M+H).

Example 36: N- (3-( 1H -pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-yloxy)- 1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide hydrochloride

Step 1: 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)aniline

In the presence of 3-bromo-5-(trifluoromethyl)aniline (1 g, 4.17 mmol) of 1,4-two Add 4,4,4',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolan) to a mixture of alkane (12 mL) Alkane) (1.164 g, 4.58 mmol), PdCl ₂ (dppf) (0.305 g, 0.417 mmol) and Cs ₂ CO ₃ (2.71 g, 8.33 mmol). The mixture was stirred at 100 ° C under nitrogen atmosphere for 2 h. The mixture was filtered and concentrated and purified by column chromatography (PE/EA = 5:1). All the fractions containing the product (PE/EA = 2:1, _Rf = 0.8) were judged by TLC to be combined and concentrated to give 3-(4,4,5,5-tetramethyl-1 as a pale yellow solid. 3,2-Dioxaborolan-2-yl)-5-(trifluoromethyl)aniline (800 mg, 2.369 mmol, 56.9% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.27 (s, 1H), 7.23 (s, 1H), 7.03 (s, 1H), 1.37 (s, 12H). ES-LCMS m/z 287.9 (M+H).

Step 2: 4-Bromo-1 H -pyrazole-1-carboxylic acid tert-butyl ester

The mixture was added Boc-pyrazole (500mg, 3.40mmol) of DCM (10mL) in ₂ O _(0.790mL, 3.40mmol) and _{Et 3 N (0.948mL, 6.80mmol)} - containing 4-bromo -1 H. The mixture was stirred at 25 ° C for 1 h. The mixture was concentrated to give 4-bromo- 1H -pyrazole-l-carboxylic acid as the butyl ester (800 mg, 2.91 mmol, 86% yield). TLC (PE/EA = 2:1, _Rf = 0.6): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.31 (s, 1H), 7.77 (s, 1H), 1.63 (s, 9H). ES-LCMS m/z 148.0 (M-Boc+H).

Step 3: 3-( 1H -pyrazol-4-yl)-5-(trifluoromethyl)aniline

Containing 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)aniline (500 mg, 1.742 mmol) 1,4-two 4-bromo-1 H -pyrazole-1-carboxylic acid tert-butyl ester (473 mg, 1.916 mmol), PdCl ₂ (dppf) (127 mg, 0.174 mmol) and a mixture of alkane (12 mL) and water (3 mL) Cs ₂ CO ₃ (1135 mg, 3.48 mmol). The mixture was stirred at 100 ° C under nitrogen atmosphere for 16 h. The mixture was filtered and concentrated and purified by column chromatography (PE/EA = 1:1). All fractions containing the product (PE/EA = 1:1, _Rf = 0.2) were judged by TLC to be combined and concentrated. Subsequent purification of the residue by preparative TLC (DCM /MeOH = 15:1, _Rf = 0.6) afforded 3-( 1H -pyrazol-4-yl)-5-(trifluoromethyl)aniline as a yellow solid. (8 mg, 0.030 mmol, 1.7% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.93 (s., 2H), 7.08 (s, 1H), 7.06 (s, 1H), 6.78 (s, 1H) ). ES-LCMS m/z 228.1 (M+H).

Step 4: N- (3-( 1H -pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-(4- Methoxybenzyloxy)pyridin-3-yl)-2-fluorophenyl)acetamide

In the presence of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (15 mg, 0.036 mmol) Add 3-( 1H -pyrazol-4-yl)-5-(trifluoromethyl)aniline (8.28 mg, 0.036 mmol) and T ₃ P ^® (EA sol) (0.5) to a mixture of pyridine (3 mL) mL, 0.036 mmol). The mixture was stirred at 25 ° C for 1 h. The mixture is added to water and concentrated to give N- (3-( 1H -pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy)- 6-((4-Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (50 mg, 0.024 mmol, 66.3% yield). TLC (DCM / MeOH = 15:1, _Rf = 0.5): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.02 (s, 1H), 7.82 (s, 1H), 7.58 (s, 1H), 7.37 ( s, 2H), 7.32-7.30 (m, 4H), 7.25-7.23 (m, 2H), 6.89-6.86 (m, 3H), 5.36 (s, 2H), 4.15-4.09 (m, 2H), 3.83 ( s, 2H), 3.77 (s, 3H), 1.46 (t, J = 6.8 Hz, 3H). ES-LCMS m/z 621.2 (M+H).

Step 5: N- (3-( 1H -pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-yloxy)- 1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide hydrochloride

Containing N- (3-(1 H -pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-(4-A) To a mixture of EtOAc (1 mL, 12. The mixture was stirred at 25 ° C for 2 h. The mixture was concentrated, added NH ₄ OH (0.5mL). The reaction residue was then concentrated and purified by preparative HPLC (column: ASB C18 150*25 mm; mobile phase A: water + 0.1% HCl; mobile phase B: MeCN; flow rate: 25 mL/min; gradient profile: 40 -70 (B%)), N- (3-( 1H -pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-B) Oxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide hydrochloride (6.95 mg, 0.013 mmol, 15.9% yield): ¹ H NMR (400MHz, CD ₃ OD) δ 8.16 (s, 2H), 8.06 (s, 1H), 7.82 (s, 1H), 7.62 (s, 1H), 7.48-7.42 (m, 1H), 7.41-7.34 (m , 3H), 7.33 (s, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.84 (s, 2H), 1.46 (t, J = 7.2 Hz, 3H). ES-LCMS m/z 501.2 (M+H). TLC (DCM / MeOH = 10:1, _Rf = 0.2).

Example 37: 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (6- (1,1 , 1-trifluoro-2-methylpropan-2-yl)pyridin-3-yl)acetamide hydrochloride

Step 1: (1 E , 4 Z )-7,7,7-trifluoro-5-hydroxy-1-methoxy-6,6-dimethylheptane-1,4-dien-3-one

Oxalyl acyl chloride (7.29mL, 83mmol) cooled to 0 ℃ containing the 3,3,3-trifluoro-2,2-dimethyl-propionic acid (10g, 64.1mmol) of CHCl ₃ (100mL) mixture of . The mixture was stirred at 70 ° C for 4 h. The mixture was then concentrated. LiHMDS (128 mL) was added dropwise to a mixture of ( E )-4-methoxybut-3-en-2-one (12.83 g, 128 mmol) in THF (100 mL) cooled to -78. , 128 mmol). The mixture was stirred at -78 °C for 1 h. A solution of 3,3,3-trifluoro-2,2-dimethylpropane chloride in THF (100 mL) was then added to the mixture at -78 °C. Let the entire mixture allowed to warm to room temperature over 2 h, using NH ₄ Cl (saturated aqueous solution, 30 mL) quenched. The THF was removed by vacuum. H ₂ O (80 mL) was added to the mixture and extracted with EA (100 mL×3). The organic layer was washed with brine (80 mL) dried over sodium sulfate. The crude product was purified by column chromatography (PE/EA = 2:1). TLC taken by the determination of the product-containing fractions it was all dissolved (PE / EA = 2: 1 , R f = 0.5) were combined to produce an off-white oil of (1 E, 4 Z) -7,7,7- trifluoro -5 -Hydroxy-1-methoxy-6,6-dimethylheptan-1,4-dien-3-one (1 g, 3.36 mmol, 5.2% yield): ¹ H NMR (400 MHz, CDCl ₃ ): δ 15.90 (s, 1H), 7.65 (d, J = 12.4 Hz, 1H), 5.63 (s, 1H), 5.33 (d, J = 12.4 Hz, 1H), 3.74 (s, 3H), 1.38 (s, 6H). ES-LCMS m/z 239.1 (M+H).

Step 2: 2-(1,1,1-Trifluoro-2-methylpropan-2-yl)-4 H -pyran-4-one

Containing (1 E , 4 Z )-7,7,7-trifluoro-5-hydroxy-1-methoxy-6,6-dimethylheptane-1,4-dien-3-one (1 g TFA (0.647 mL, 8.40 mmol) was added to a mixture of toluene (5 mL). The mixture was stirred at 25 ° C for 16 h. The mixture was then concentrated to give 2- (1,1,1-trifluoro-2-methylpropan-2-yl) -4 H - pyran-4-one (800mg, 3.10mmol, 73.9% yield). TLC (PE/EA = 1:1, R _f = 0.2): ¹ H NMR (400 MHz, CD ₃ OD): δ 8.12 (d, J = 6.0 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H) ), 6.39 (dd, J = 2.4, 6.0 Hz, 1H), 1.53 (s, 6H). ES-LCMS m/z 207.1 (M+H).

Step 3: 2-(1,1,1-Trifluoro-2-methylpropan-2-yl)pyridine-4(1 H )-one

A mixture of 2- (1,1,1-trifluoro-2-methylpropan-2-yl) -4 H - pyran-4-one (800mg, 3.88mmol) of NH ₄ OH (8mL, 205mmol) a mixture of Stir at 90 ° C for 1 h. The mixture was then concentrated and triturated and filtered using MeOH (20 mL). The filtrate was concentrated and purified by flash column chromatography (DCM /MeOH = 9:1). All the fractions (DCM/MeOH = 9:1, R _f = 0.2) containing the product were judged by TLC to be combined and concentrated to give 2-(1,1,1-trifluoro-2-methyl as a yellow oil. Propane-2-yl)pyridine-4( 1H )-one (700 mg, 2.90 mmol, 74.7% yield): ¹ H NMR (400 MHz, CD ₃ OD): δ 7.87 (d, J = 7.2 Hz, 1H) , 6.70 (d, J = 2.4 Hz, 1H), 6.54 (dd, J = 2.4, 7.2 Hz, 1H), 1.60 (s, 6H). ES-LCMS m/z 206.1 (M+H).

Step 4: 5-Nitro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4(1 H )-one

a mixture of H ₂ SO ₄ (8 mL, 150 mmol) containing 2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4( 1H )-one (300 mg, 1.462 mmol) Nitric acid (3.27 mL, 73.1 mmol) was added. The mixture was stirred at 90 ° C for 15 h. The mixture was then added to ice water and made basic with aqueous NaOH. The mixture was filtered. The filtrate and purification by preparative TLC (DCM / MeOH = 9: 1, R f = 0.1) was concentrated to give a light yellow solid of 5-nitro-2- (1,1,1-trifluoro-2-methyl Propane-2-yl)pyridine-4( 1H )-one (100 mg, 0.380 mmol, 26.0% yield): ¹ H NMR (400 MHz, CD ₃ OD): δ 8.82 (s, 1H), 6.95 (s, 1H), 1.64 (s, 6H). ES-LCMS m/z 251.1 (M+H).

Step 5: 4-Bromo-5-nitro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine

a mixture of DCE (10 mL) containing 5-nitro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine-4( 1H )-one (100 mg, 0.400 mmol) Phosphorus tribromide (138 mg, 0.480 mmol) was added. The mixture was stirred at 85 ° C for 1 h. The mixture was then added to an aqueous NaHCO ₃ solution. The mixture was extracted using EA (50 mL x 2). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated to afford 4-bromo-5-nitro-2-(1,1,1-trifluoro-2-methylpropan-2-yl) Pyridine (60 mg, 0.096 mmol, 24.0% yield). TLC (PE/EA = 10:1, _Rf = 0.6): ¹ H NMR (400 MHz, CD ₃ OD): δ 8.74 (s, 1H), 6.83 (s, 1H), 1.54 (s, 6H). ES-LCMS m/z 312.9 (M+H).

Step 6: 4-Bromo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-3-amine

Addition of chlorination to a mixture of 4-bromo-5-nitro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridine (50 mg, 0.160 mmol) in EtOH (10 mL) Tin (II) dihydrate (180 mg, 0.799 mmol). The mixture was stirred at 85 ° C for 16 h. The mixture was then added to an aqueous NaHCO ₃ solution. The mixture was extracted using EA (50 mL x 2). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (PE / EA = 2: 1, R f = 0.5) yielded the pale yellow solid of 4-bromo-6- (1,1,1-trifluoro-2-methyl-propyl-2 - pyridine-3-amine (30 mg, 0.090 mmol, 56.4% yield): ¹ H NMR (400 MHz, CD ₃ OD): δ 8.05 (s, 1H), 7.58 (s, 1H), 1.56 (s, 6H). ES-LCMS m/z 283.1 (M+H).

Step 7: N- (4-Bromo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-3-yl)-2-(4-(4-ethoxy) -6-((4-Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide

In the presence of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (30 mg, 0.073 mmol) 4-Bromo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-3-amine (20.64 mg, 0.073 mmol) and T ₃ P ^® were added to a mixture of pyridine (5 mL) (EA solvate) (0.5 mL, 0.073 mmol). The mixture was stirred at 25 ° C for 1 h. The mixture was concentrated and purified by preparative TLC (DCM / MeOH = 15: 1, R f = 0.6) yielded the pale yellow solid of N - (4- bromo-6- (1,1,1-trifluoro-2- Propane-2-yl)pyridin-3-yl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2- Fluorophenyl)acetamide (30 mg, 0.038 mmol, 51.7% yield): ¹ H NMR (400 MHz, CD ₃ OD): δ 8.84 (s, 1H), 7.99 (s, 1H), 7.90 (s, 1H) ), 7.46 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 9.6 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 6.48(s,1H), 5.30(s,2H), 4.16(q, J =6.8Hz,2H),3.93(s,2H),3.82(s,3H),1.63(s,6H),1.40(t , J = 7.0Hz, 3H). ES-LCMS m/z 678.0 (M+H+2).

Step 8: 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (6- (1,1 , 1-trifluoro-2-methylpropan-2-yl)pyridin-3-yl)acetamide hydrochloride

In the presence of N- (4-bromo-6-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-3-yl)-2-(4-(4-ethoxy-) Add Pd/C (4 mg) to a mixture of 6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (30 mg, 0.044 mmol) in DCM (10 mL) , 0.038 mmol). The mixture was stirred at 25 ° C under H ₂ atmosphere for 72 h. The mixture was filtered and concentrated. The crude product was purified by preparative HPLC (column: ASB C18 150*25mm; mobile phase A: water + 0.1% HCl; mobile phase B: MeCN flow rate: 25 mL/min; gradient profile: 45-75 (B%) ), to produce an off-white solid of 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (6- ( 1,1,1-Trifluoro-2-methylpropan-2-yl)pyridin-3-yl)acetamide hydrochloride (7.91 mg, 0.015 mmol, 34.6% yield). TLC (DCM / MeOH = 9:1, _Rf = 0.2): ¹ H NMR (400 MHz, CD ₃ OD): δ 9.08 (d, J = 2.0 Hz, 1H), 8.32 (dd, J = 2.4, 8.8 Hz , 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.81 (s, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.34 - 7.27 (m, 2H), 6.39 (s, 1H) , 4.25 (q, J = 7.2 Hz, 2H), 3.89 (s, 2H), 1.69 (s, 6H), 1.41 (t, J = 7.2 Hz, 3H). ES-LCMS m/z 478.1 (M+H).

Example 38: N- (4-Cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-o-oxy-1,6-dihydropyridine-3 -yl)-2-fluorophenyl)acetamide

Step 1: N- (4-Cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)) -pyridin-3-yl)-2-fluorophenyl)acetamide

In the presence of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (1 g, 2.431 mmol) T ₃ P ^® (4.64 g, 7.29 mmol) was slowly added to a solution of 4-amino-2-(trifluoromethyl)benzonitrile (0.452 g, 2.431 mmol) in pyridine (3.93 mL, 48.6 mmol). The mixture was stirred at room temperature for 0.5 h. Using H ₂ O (10mL) quenched, extracted with DCM (20mL x 5). The combined organic extracts were dehydrated, filtered, and concentrated. Purified by column chromatography (PE/EA = 5/1, R _f = 0.6) to give N- (4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(4- Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (870 mg, 1.351 mmol, 55.6% yield). ¹ H NMR (400 MHz, CDCl ₃ - d ): δ 8.02 (s, 1H), 7.78 (s, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H) , 7.30-7.45 (m, 5H), 6.93 (d, J = 8 Hz, 2H), 6.33 (s, 1H), 5.33 (d, J = 8 Hz, 2H), 4.09 (q, J = 6.8 Hz, 2H) , 3.83 (s, 5H), 1.41 (t, J = 6.8 Hz, 3H); LCMS (m/z): 580.0 (M+H).

Step 2: N- (4-Cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-o-oxy-1,6-dihydropyridine-3 -yl)-2-fluorophenyl)acetamide

Containing N- (4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-(4-methoxyphenyl) at 0 °C To a solution of oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (870 mg, 1.501 mmol) in EtOAc (EtOAc) The mixture was stirred at room temperature for 1 h. Using a mixture of _{NH 4 OH (5mL, 20%} ) was basified to pH = 8, was filtered, the solid was used to produce H ₂ O (5mL) and was washed and dried to give the product N - (4- cyano-3- (trifluoromethyl Phenyl)-2-(4-(4-ethoxy-6-oxooxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide (462.91 mg, 0.973mmol, 64.8% ^{yield): 1 H NMR (400MHz,} CD 3 OD): δ 8.24 (s, 1H), 7.96-8.05 (m, 1H), 7.90-7.96 (m, 1H), 7.36-7.40 ( m, 2H), 7.20-7.28 (m, 2H), 6.00 (s, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.85 (s, 2H), 1.38 (t, J = 7.2 Hz, 3H) ): LCMS (m/z): 459.9 (M+H).

Example 39: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (2- you Polinylethoxy)-5-(trifluoromethyl)phenyl)acetamide

Step 1: 4-(2-(3-Nitro-5-(trifluoromethyl)phenoxy)ethyl)morpholine

1-Fluoro-3-nitro-5-(trifluoromethyl)benzene (800 mg, 3.83 mmol), 2-morpholinylethanol (552 mg, 4.21 mmol) and K ₂ CO ₃ (1586 mg, 11.48 mmol) The DMF (20 mL) mixture was stirred at 90 ° C for 10 h. The mixture was concentrated. DCM (150 mL) was added to the residue, and the mixture was stirred for 10 min and then filtered. The filtrate was concentrated. The residue was purified by vermiculite column chromatography (PE/EA=10:1~5:1). All fractions containing the product (PE/EA = 5:1, _Rf = 0.6) were judged by TLC to be combined and concentrated to give 4-(2-(3-nitro-5-(trifluoromethyl) as a yellow solid. Phenoxy)ethyl)morpholine (600 mg, 1.780 mmol, 46.5% yield): ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.02 (s, 1H), 7.78 (s, 1H), 7.43 (s) , 1H), 4.16 (t, J = 5.6 Hz, 2H), 3.72-3.63 (m, 4H), 2.79 (t, J = 5.6 Hz, 2H), 2.58-2.47 (m, 4H). ES-LCMS m/z : 321 (M+H).

Step 2: 3-(2-morpholinylethoxy)-5-(trifluoromethyl)aniline

Add to a mixture of 4-(2-(3-nitro-5-(trifluoromethyl)phenoxy)ethyl)morpholine (600 mg, 1.873 mmol) in MeOH (50 mL) Pd/C (19.94 mg, 0.187 mmol). The mixture was stirred at 25 ° C for 5 h under H ₂ atmosphere. The mixture was filtered, and the filtrate was concentrated to give a yellow oil of 3- (2-morpholino-ethoxy) -5- (trifluoromethyl) aniline (500mg, 1.490mmol, 80% yield): ¹ H NMR (400MHz, CDCl ₃ ): δ 6.52 (d, J = 9.2 Hz, 2H), 6.35 (s, 1H), 4.12-4.02 (m, 2H), 3.82 (s, 2H), 3.76-3.66 (m, 4H) ), 2.78 (t, J = 5.6 Hz, 2H), 2.57 (d, J = 4.0 Hz, 4H). ES-LCMS m/z : 291 (M+H).

Step 3: 2- (4- (5-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (3- ( 2-morpholinyl-ethoxy)-5-(trifluoromethyl)phenyl)acetamide

In the presence of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (70.9 mg, 0.172 mmol) T ₃ P ^® (50% in EA, 0.3 mL) was added dropwise to a mixture of 3-(2-morpholinylethoxy)-5-(trifluoromethyl)aniline (50 mg, 0.172 mmol) in pyridine (5 mL) The mixture was stirred at 25 ° C for 1 h. The mixture was quenched with cold water (20 mL) and extracted with DCM / MeOH (10:1, v / v , 20mL x 3). The organic layer was dried over sodium sulfate and concentrated to give 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2- fluorophenyl) - N - (3- (2- morpholino-ethoxy) -5- (trifluoromethyl) phenyl) acetyl amine (80mg, 0.111mmol, 64.5% yield): ¹ H NMR (400 MHz, CD ₃ OD): δ 7.94 (d, J = 1.8 Hz, 1H), 7.54 (s, 1H), 7.48 (s, 1H), 7.45-7.35 (m, 6H), 6.95-6.88 (m , 3H), 5.35 (s, 2H), 4.20-4.10 (m, 4H), 3.80 (s, 2H), 3.78 (s, 3H), 3.73-3.66 (m, 4H), 2.81 (t, J = 5.4 Hz, 2H), 2.59 (d, J = 4.2 Hz, 4H), 1.41 (t, J = 6.8 Hz, 3H). ES-LCMS m/z : 684 (M+H).

Step 4: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (2- you Polinylethoxy)-5-(trifluoromethyl)phenyl)acetamide

A mixture of 2- (4- (5-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (3- (2 A mixture of morpholinylethoxy)-5-(trifluoromethyl)phenyl)acetamide (80 mg, 0.117 mmol) and TFA (10 mL, 10% DCM) was stirred at 25 ° C for 2 h. The mixture was concentrated. NH ₃ (6 mol/L MeOH solution, 1 mL) was added to the residue and concentrated. The residue was purified by preparative TLC (DCM / MeOH = 15:1, _Rf = 0.4) to yield 2-(4-(5-ethoxy-6-s. pyridin-3-yl) -2-fluorophenyl) - N - (3- (2- morpholino-ethoxy) -5- (trifluoromethyl) phenyl) acetyl amine (35.72mg, 0.061mmol , 51.7% yield): ¹ H NMR (400MHz, CD ₃ OD): δ 7.59 (s, 1H), 7.46 (s, 1H), 7.43-7.37 (m, 1H), 7.36-7.30 (m, 2H) , 7.29 (d, J = 2.0 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 6.96 (s, 1H), 4.23 (t, J = 5.2 Hz, 2H), 4.11 (q, J = 6.8 Hz, 2H), 3.79 (s, 2H), 3.78-3.69 (m, 4H), 3.02-3.00 (m, 2H), 2.80-2.79 (m, 4H), 1.45 (t, J = 6.8 Hz, 3H) ). ES-LCMS m/z : 564 (M+H).

Example 40: 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (1,1 , 1-trifluoro-2-methylpropan-2-yl) Oxazol-5-yl)acetamide

Step 1: 2- (4- (4-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (3- ( 1,1,1-trifluoro-2-methylpropan-2-yl) Oxazol-5-yl)acetamide

In the presence of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (1.060 g, 2.58 mmol) Different from 3-(1,1,1-trifluoro-2-methylpropan-2-yl) T ₃ P ^® (50% EA solution, 5 mL, 2.58 mmol) was added dropwise to a mixture of pyridine-5-amine (0.5 g, 2.58 mmol) in pyridine (20 mL) and stirred at 25 ° C for 1 h. The mixture was poured into cold water (100 mL) with stirring. The mixture was stirred for 0.5 h and allowed to stand for 10 h. The resulting solid was filtered, using H ₂ O (200mL x 3) and TBME (200mL x 2), dried, and vacuum dried to give an off-white solid 2- (4- (4-ethoxy-6 - ((4-methoxy benzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (3- (1,1,1- trifluoro-2-methylpropan-2-yl) iso Imidazole-5-yl)acetamide (1.5 g, 2.298 mmol, 89% yield): ¹ H NMR (400 MHz, CD ₃ OD): δ 7.96 (s, 1H), 7.40-7.32 (m, 3H), 7.28 (d, J = 9.6 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 6.45 (s, 1H), 6.38 (s, 1H), 5.27 (s, 2H), 4.12 (q, J) = 7.2 Hz, 2H), 3.83 (s, 2H), 3.79 (s, 3H), 1.53 (s, 6H), 1.37 (t, J = 6.8 Hz, 3H). ES-LCMS m/z : 588 (M+H).

Step 2: 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (1,1 , 1-trifluoro-2-methylpropan-2-yl) Oxazol-5-yl)acetamide

Containing 2- (4- (4-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (3- (1 , 1,1-trifluoro-2-methylpropan-2-yl) To a suspension of oxazol-5-yl)acetamide (1.5 g, 2.55 mmol) in EtOAc (EtOAc) The mixture was stirred at 25 ° C for 2 h. The mixture was then concentrated. H ₂ O (50 mL) was added dropwise to the residue, and the mixture was neutralized with a saturated Na ₂ CO ₃ solution to adjust to pH = 7.5. The precipitate was filtered, using H ₂ O (50mL x 3), dried, and dried in vacuo. PE/EA (3:1, v / v , 30 mL) was added to the solid and stirred for 0.5 h. The solid was filtered and washed with PE/EA (3:1, v / v , 30mL x 2). The solid was redissolved in DCM / MeOH (20:1, v / v , 50mL) The solid was filtered, using CH ₃ CN (10mL x 2) washed, and dried in vacuo. The residue was redissolved in DCM / MeOH (10:1, v / v , 50mL). hydrogen pyridin-3-yl) -2-fluorophenyl) - N - (3- (1,1,1- trifluoro-2-methylpropan-2-yl) iso Imidazole-5-yl)acetamide (440 mg, 0.938 mmol, 36.7% yield): ¹ H NMR (400 MHz, CD ₃ OD): δ 7.39-7.36 (m, 1H), 7.36-7.30 (m, 1H) , 7.25-7.18 (m, 2H), 6.37 (s, 1H), 5.99 (s, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.82 (s, 2H), 1.53 (s, 6H), 1.37 (t, J = 6.8 Hz, 3H). ES-LCMS m/z : 468 (M+H); </ RTI><RTIID=0.0></RTI><RTIgt;

Example 41: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (1- methyl-3 -(1,1,1-trifluoro-2-methylpropan-2-yl)-1 H -pyrazol-5-yl)acetamide hydrochloride

Step 1: 5,5,5-Trifluoro-4,4-dimethyl-3-oxo-valeronitrile

n- BuLi (17.63 mL, 44.1 mmol) was added to a mixture of EtOAc (EtOAc:EtOAc. The mixture was stirred at -30 ° C for 0.5 h. Then, 3,3,3-trifluoro-2,2-dimethylpropionic acid methyl ester (5 g, 29.4 mmol) was added dropwise to the mixture. The mixture was stirred for a further 1 h. Mixture with saturated NH ₄ Cl solution (50mL) The reaction was quenched and extracted with EA (100mL x 2). The organic layer was dried over sodium sulfate, filtered and concentrated to afford 5,5,5-trifluoro-4,4-dimethyl-3-oxoxypenteronitrile (3 g, 16.75 mmol, 57.0% yield Rate: ¹ H NMR (400 MHz, CD ₃ OD): δ 3.75 (s, 2H), 1.40 (s, 6H).

Step 2: 1-Methyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1 H -pyrazole-5-amine

Add methyl hydrazine (3.33 g, 28.9 mmol) to a mixture of 5,5,5-trifluoro-4,4-dimethyl-3-oxoxyvaleronitrile (1 g, 5.58 mmol) in EtOH (10 mL) Concentrated HCl (0.5 mL). The mixture was then stirred at 100 ° C for 18 h. Between the mixture was then concentrated, the residue fraction produced was dissolved DCM (20mL) and H ₂ O (10mL), using DCM (20mL x 2) and extracted. The combined organic extracts were washed with brine (20 mL) The crude product was purified by fluorite column chromatography (40% EA: 60% PE, 12 g. All the fractions containing the product (EA: PE = 1:2, _Rf = 0.2) were judged by TLC to be combined and concentrated to give 1-methyl-3-(1,1,1-trifluoro-2 as a white solid. -Methylpropan-2-yl)-1 H -pyrazole-5-amine (500 mg, 2.293 mmol, 41.1% yield): ¹ H NMR (400 MHz, CD ₃ OD): δ 5.48 (s, 1H), 3.56 (s, 3H), 1.42 (s, 6H). ES-LCMS m/z 208 (M+H).

Step 3: 2- (4- (5-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (1- A 3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1 H -pyrazol-5-yl)acetamide

2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (150 mg) at 25 ° C , 0.365 mmol), 1-methyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1 H -pyrazole-5-amine (83 mg, 0.401 mmol) pyridine (3mL) was added a mixture of T ₃ P ^® (EA solvate) (0.3mL, 0.365mmol). The mixture was then stirred for 2h, the mixture was concentrated, between (20mL) and H ₂ O (10mL) to generate the residue was dissolved in DCM points, extracted with DCM (20mL x 2). The combined organic extracts were washed with brine (20 mL EtOAc EtOAc oxy) pyridin-3-yl) -2-fluorophenyl) - N - (1- methyl-3- (1,1,1-trifluoro-2-methylpropan-2-yl) -1 H - Pyrazol-5-yl)acetamide (150 mg, 0.225 mmol, 61.7% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.52 (d, J = 4.4 Hz, 1H), 7.94 (d, J =2.0 Hz, 1H), 7.44-7.41 (m, 3H), 7.39 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 6.27 (s, 1H), 5.35 (s , 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.83 (s, 2H), 3.78 (s, 3H), 3.72-3.67 (m, 3H), 1.47 (s, 6H), 1.41 (t, J = 7.0 Hz, 3H). ES-LCMS m/z 601 (M+H).

Step 4: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (1- methyl-3 -(1,1,1-trifluoro-2-methylpropan-2-yl)-1 H -pyrazol-5-yl)acetamide hydrochloride

A mixture of 2- (4- (5-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (1- methyl TFA ▪ DCM (soluble in -3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1 H -pyrazol-5-yl)acetamide (150 mg, 0.250 mmol) (10 mL, 10%) mixture was stirred at 25 ° C for 0.5 h. The mixture is then concentrated and the residue is purified by preparative HPLC (column: ASB C18 150*25mm / mobile phase A: water (water + 0.1% HCl) / mobile phase B: acetonitrile / gradient: 37-67 (B% / flow rate: 25 mL / min / operating time: 15 min), yielding 2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorobenzene yl) - N - (1- methyl-3- (1,1,1-trifluoro-2-methylpropan-2-yl) -1 H - pyrazol-5-yl) acetyl amine hydrochloride (83.1 mg, 0.160 mmol, 63.9% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.48-7.41 (m, 1H), 7.39 (s, 1H), 7.37 (d, J = 3.5 Hz, 1H) ), 7.33 (d, J = 2.0 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 6.29 (s, 1H), 4.15 (q, J = 7.0 Hz, 2H), 3.86 (s, 2H) ), 3.73 (s, 3H), 1.51 (s, 6H), 1.50-1.45 (m, 3H). ES-LCMS m/z 481 (M+H).

Example 42: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (1,1 , 1-trifluoro-2-methylpropan-2-yl)-1 H -pyrazol-5-yl)acetamide hydrochloride

Step 1: 5,5,5-Trifluoro-4,4-dimethyl-3-oxo-valeronitrile

n- BuLi (17.63 mL, 44.1 mmol, 2.5 mol/L) was added to a mixture of acetonitrile (3.22 g, 44.1 mmol) in THF (60 mL). The mixture was stirred at -30 ° C for 0.5 h. Then, 3,3,3-trifluoro-2,2-dimethylpropionic acid methyl ester (5 g, 29.4 mmol) was added dropwise to the mixture. The mixture was then stirred for a further 1 h. Mixture with saturated NH ₄ Cl solution (50mL) quenched, extracted with EA (100mL x 2). The organic layer was dried over sodium sulfate, filtered and concentrated to afford 5,5,5-trifluoro-4,4-dimethyl-3-oxoxypenteronitrile (3 g, 16.75 mmol, 57.0 % yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 3.75 (s, 2H), 1.40 (s., 6H).

Step 2: 3-(1,1,1-Trifluoro-2-methylpropan-2-yl)-1 H -pyrazole-5-amine

Add hydrazine (1.263 g, 33.5 mmol) to a mixture of EtOH (10 mL) containing 5,5,5-trifluoro-4,4-dimethyl-3-oxoxyvaleronitrile (2 g, 11.16 mmol) HCl (0.5 mL). The mixture was then stirred at 100 ° C for 18 h. The mixture was then concentrated and the residue was partitioned between DCM (20 <RTI ID=0.0></RTI><RTIgt_; The combined organic extracts were washed with brine (20 mL) The crude product was purified by fluorite column chromatography (100% EA, 12 g. All the fractions (EA, R _f = 0.3) containing the product were judged by TLC to be combined and concentrated to give 3-(1,1,1-trifluoro-2-methylpropan-2-yl) as an off white oil. -1 H - pyrazol-5-amine (500mg, 2.459mmol, 22.03% ^{yield): 1 H NMR (400MHz,} CD 3 OD) δ 5.58 (s, 1H), 1.47 (s, 6H). ES-LCMS m/z 194 (M+H).

Step 3: 2- (4- (5-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (3- ( 1,1,1-trifluoro-2-methylpropan-2-yl)-1 H -pyrazole-5-yl)acetamide

2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (100 mg) at 25 ° C a mixture of 0.243 mmol) and pyridine (3 mL) with 3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1 H -pyrazol-5-amine (51.6 mg, 0.267 mmol) T ₃ P ^® (EA lysate) (0.3 mL, 0.243 mmol) was added. The mixture was then stirred for 2h, the mixture was concentrated, between (20mL) and H ₂ O (10mL) to generate the residue was dissolved in DCM points, extracted with DCM (20mL x 2). The combined organic extracts were washed with brine (20 mL EtOAc EtOAc oxy) pyridin-3-yl) -2-fluorophenyl) - N - (3- (1,1,1- trifluoro-2-methylpropan-2-yl) -1 H - pyrazol-5 Ethylamine (100 mg, 0.102 mmol, 42.1% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.52 (d, J = 4.2 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H) ), 7.48-7.33 (m, 6H), 6.90 (d, J = 8.6 Hz, 2H), 5.35 (s, 2H), 4.19-4.09 (m, 2H), 3.78 (s, 3H), 3.70-3.63 ( m, 2H), 1.54-1.36 (m, 9H). ES-LCMS m/z 587 (M+H).

Step 4: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (1,1 , 1-trifluoro-2-methylpropan-2-yl)-1 H -pyrazol-5-yl)acetamide hydrochloride

A mixture of 2- (4- (5-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (3- (1 ,1,1-trifluoro-2-methylpropan-2-yl)-1 H -pyrazol-5-yl)acetamidine (100 mg, 0.170 mmol) in TFA, DCM (methanol) (10 mL, 10%) The mixture was stirred at 25 ° C for 0.5 h. The mixture was then concentrated and the residue was purified by preparative HPLC (column: ASB C18 150*25mm / mobile phase A: water (water + 0.1% HCl) / mobile phase B: acetonitrile / gradient: 33-63 (B% / flow rate: 25 mL / min / operating time: 15 min), yielding a white solid of 2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2 - fluorophenyl) - N - (3- (1,1,1- trifluoro-2-methylpropan-2-yl) -1 H - pyrazol-5-yl) acetyl amine hydrochloride (43.33 Mg, 0.084 mmol, 49.2% yield): 1H NMR (400 MHz, DMSO- d 6) δ 11.81 (s, 1H), 10.68 (s, 1H), 7.46-7.28 (m, 5H), 7.11 (d, J =2.0 Hz, 1H), 6.41 (s, 1H), 4.03 (q, J = 6.8 Hz, 2H), 3.66 (s, 2H), 1.45 (s, 6H), 1.32 (t, J = 6.9 Hz, 3H) ). ES-LCMS m/z 467 (M+H).

Example 43: N- (4-(2,2-Difluoro-3-hydroxypropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-side) Oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide

Step 1: 2,2-Difluoro-3-(2-(trifluoromethyl)phenyl)propanoic acid ethyl ester

Add 2,2-difluoro-2-iodoacetic acid to a mixture of 1-(bromomethyl)-2-(trifluoromethyl)benzene (0.5 g, 2.092 mmol) in DMSO (10 mL) at room temperature Ethyl ester (0.410 mL, 2.000 mmol) and copper (0.439 g, 6.90 mmol). The mixture was stirred at 20 ° C for 10 h. The mixture was extracted with EA, washed with brine and brine, and then evaporated to give ethyl 2,2-difluoro-3-(2-(trifluoromethyl)phenyl)propanoate (320 mg, 0.981 mmol, 46. Rate): ¹ H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 7.72 (d, J = 7.8 Hz, 1H), 7.60-7.45 (m, 3H), 4.26 (d, J = 7.1 Hz, 2H), 3.63 (t, J = 16.9 Hz, 2H), 1.24 (t, J = 7.2 Hz, 3H).

Step 2: Ethyl 2,2-difluoro-3-(4-nitro-2-(trifluoromethyl)phenyl)propanoate

, Was added 2,2-difluoro-containing-3- (2- (trifluoromethyl) phenyl) propanoate (250mg, 0.886mmol) of H ₂ SO ₄ (5mL) mixture at room temperature Potassium nitroperoxylate (99 mg, 0.974 mmol). The mixture was stirred at 20 ° C for 2 h. TLC (PE/EA = 5:1, _Rf = 0.6) showed that the reaction was completed. The mixture was poured into ice-water. The mixture was extracted with EA (10 mL x 3) and washed with water. The organic layer was concentrated to give ethyl 2,2-difluoro-3-(4-nitro-2-(trifluoromethyl)phenyl)propanoate (230 mg, 0.643 mmol, 72.6% yield): ¹ H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 8.56 (d, J = 2.2 Hz, 1H), 8.48 (dd, J = 2.4, 8.6 Hz, 1H), 7.86 (d, J = 8.6 Hz, 1H) , 4.31 (q, J = 7.1 Hz, 2H), 3.80 (t, J = 17.0 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H).

Step 3: 3-(4-Amino-2-(trifluoromethyl)phenyl)-2,2-difluoropropionic acid ethyl ester

Ethyl 2,2-difluoro-3-(4-nitro-2-(trifluoromethyl)phenyl)propanoate (220 mg, 0.672 mmol) in MeOH (10 mL) Pd/C (71.6 mg, 0.672 mmol) was added to the mixture. The mixture was then stirred under H ₂ atmosphere for 1 h. LCMS and TLC (PE/EA = 5:1, _Rf = 0.3) showed that the reaction was completed. The mixture was filtered and the filtrate was evaporated to purified crystals crystals ¹ H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 7.15 (s, 1H), 6.97 (d, J = 2.2 Hz, 1H), 6.81 (dd, J = 2.1, 8.4 Hz, 1H), 4.24 (q) , J = 7.1 Hz, 2H), 3.42 (t, J = 16.8 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H). ES-LCMS m/z 298 (M+H).

Step 4: 3-(4-(2-(4-(5-ethoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl) Ethylamino)-2-(trifluoromethyl)phenyl)-2,2-difluoropropionic acid ethyl ester

In the presence of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (150 mg, 0.365 mmol) Add 3-(4-Amino-2-(trifluoromethyl)phenyl)-2,2-difluoropropionic acid ethyl ester (108 mg, 0.365 mmol) to T ₃ P ^® (pyridine (2 mL)) EA solvate) (464 mg, 0.729 mmol). The mixture was stirred at 20 ° C for 1 h. LCMS and TLC (PE/EA = 1:1, _Rf = 0.5) showed that the reaction was completed. The mixture was concentrated and purified using TLC (PE/EA = 1:1, _Rf = 0.5) to yield 3-(4-(4-(4-(5-ethoxy)-6-((4-methoxy)) Phenylmethyl)oxy)pyridin-3-yl)-2-fluorophenyl)ethylamino)-2-(trifluoromethyl)phenyl)-2,2-difluoropropionic acid ethyl ester (120 mg , 0.150 mmol, 41.2% yield): ¹ H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 8.08-8.02 (m, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.78 (s, 1H) ), 7.54 - 7.33 (m, 7H), 6.90 (d, J = 8.8 Hz, 2H), 5.35 (s, 2H), 4.26 (q, J = 7.3 Hz, 2H), 4.13 (q, J = 7.1 Hz) , 2H), 3.81 (s, 2H), 3.78 (s, 3H), 3.63-3.52 (m, 2H), 1.41 (t, J = 7.1 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H) ;ES-LCMS m/z 691 (M+H).

Step 5: N- (4-(2,2-Difluoro-3-hydroxypropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-() (4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide

3-(4-(2-(4-(5-ethoxybenzyl)oxy)pyridin-3-yl)-2-fluoro) at 0 ° C Addition of LAH (5.50 mg) to a mixture of phenyl)ethylamino)-2-(trifluoromethyl)phenyl)-2,2-difluoropropionate (100 mg, 0.145 mmol) in THF (5 mL) , 0.145 mmol). The mixture was stirred for 1 h. LCMS and TLC (PE/EA = 1:1, _Rf = 0.2) showed that the reaction was completed. The reaction was quenched with water (0.3 mL). The mixture is filtered and the filtrate is concentrated to give N- (4-(2,2-difluoro-3-hydroxypropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy) -6-((4-Methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (80 mg, 0.104 mmol, 71.6% yield): ¹ H NMR (400 MHz , CD ₃ OD-d ₄ ) δ 8.01 (s, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H) ), 7.47-7.27 (m, 6H), 6.90 (d, J = 8.8 Hz, 2H), 5.35 (s, 2H), 4.22-4.11 (m, 2H), 3.82-3.75 (m, 3H), 3.67 ( t, J = 13.0 Hz, 2H), 3.47-3.37 (m, 2H), 3.37-3.34 (m, 2H), 1.41 (t, J = 7.1 Hz, 3H). ES-LCMS m/z 649 (M+H).

Step 6: N- (4-(2,2-Difluoro-3-hydroxypropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-side) Oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide

In the presence of N- (4-(2,2-difluoro-3-hydroxypropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-(( To a mixture of 4-methoxybenzyloxy)pyridin-3-yl)-2-fluorophenyl)acetamide (50 mg, EtOAc, EtOAc) The mixture was stirred at 20 ° C for 1 h. LCMS showed the reaction was completed. The mixture was concentrated and the crude product was purified by preparative HPLC (column: ASB C18 150*25mm; mobile phase A: water + 0.1% HCl; mobile phase B: MeCN; flow rate: 25 mL/min; gradient profile: 26 -56 (B%)), yielding N- (4-(2,2-difluoro-3-hydroxypropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-B) Oxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide (16.72 mg, 0.032 mmol, 41.0% yield): ¹ H NMR (400 MHz, CD ₃ OD-d ₄ ) δ 8.01 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1H) , 7.36-7.26 (m, 3H), 7.23 (s, 1H), 4.12 (d, J = 7.1 Hz, 2H), 3.80 (s, 2H), 3.68 (t, J = 12.8 Hz, 2H), 3.41 ( t, J = 17.1 Hz, 2H), 1.45 (t, J = 6.9 Hz, 3H). ES-LCMS m/z 529 (M+H).

Example 44: N- (3-( 2H -tetrazol-5-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-yloxy)- 1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide

Step 1: 3-Nitro-5-(trifluoromethyl)benzhydryl chloride

At 20 ℃, containing nitro-5- (trifluoromethyl) benzoic acid (2g, 8.51mmol) of DCM (30mL) was added a mixture of SOCl ₂ (1.242mL, 17.0lmmol). The mixture was stirred at 20 ° C for 2 h. TLC (PE/EA = 2:1, _Rf = 0.3) showed that the reaction was completed. The mixture was concentrated to give 3-nitro-5-(trifluoromethyl)benzhydrin chloride (1.8 g, 6.50 mmol, 76% yield).

Step 2: 3-Nitro-5-(trifluoromethyl)benzamide

Add NH ₄ OH (2.96 mL, 21.30 mmol) to a mixture of 3-nitro-5-(trifluoromethyl)benzoguanidine chloride (1.8 g, 7.10 mmol) in THF (20 mL). . The mixture was stirred at 20 ° C for 12 h. LCMS showed the reaction was completed. The mixture was extracted with EA, washed with water and concentrated to give 3-nitro-5-(trifluoromethyl)benzamide (1.5 g, 5.86 mmol, 83% yield): ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 8.91 (s, 1H), 8.62 (br.s, 2H), 8.53 (s, 1H), 7.93 (s., 1H). ES-LCMS m/z 235 (M+H).

Step 3: 3-Nitro-5-(trifluoromethyl)benzonitrile

At 20 ℃, Et ₃ N was added to the mixture containing 3-nitro-5- (trifluoromethyl) benzoyl amine (1.5g, 6.41mmol) of DCM (20mL) in (1.314mL, 9.61mmol) and Trifluoroacetic acid anhydride (1.357 mL, 9.61 mmol). The mixture was stirred at 20 ° C for 2 h. TLC (PE/EA = 3:1, _Rf = 0.6) showed that the reaction was completed. The reaction was concentrated and the crude product was purified by column chromatography (PE/EA=3:1, _Rf =0.6) to yield 3-nitro-5-(trifluoromethyl)benzonitrile (1.2 g, 5.14) mmol, 80% ^{yield): 1 H NMR (400MHz,} CDCl 3 -d) δ 8.71 (s, 2H), 8.24 (s, 1H).

Step 4: 5-(3-Nitro-5-(trifluoromethyl)phenyl)-2 H -tetrazole

Sodium azide (361 mg, 5.55 mmol) was added to a mixture of 3-nitro-5-(trifluoromethyl)benzonitrile (400 mg, 1.851 mmol). The mixture was stirred at 120 ° C overnight. LCMS showed the reaction was completed. Stop using water. Using a mixture of EA (20mL x 3) was extracted, washed with water, and concentrated to give 5- (3-nitro-5- (trifluoromethyl) phenyl) -2 H - tetrazole (220mg, 0.743mmol, 40.1 % yield): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 1H), 8.73 (s, 1H), 8.66 (s, 1H), 7.92 (s, 1H). ES-LCMS m/z 260 (M+H).

Step 5: 3-( 2H -tetrazol-5-yl)-5-(trifluoromethyl)aniline

Under a nitrogen gas mask, containing 5- (3-nitro-5- (trifluoromethyl) phenyl) -2 H - added Pd / C (10mL) mixture of tetrazole (220mg, 0.849mmol) in MeOH of (45.2 mg, 0.424 mmol). The mixture was stirred at 20 ° C under H ₂ atmosphere for 1 h. LCMS showed the reaction was completed. The mixture was filtered, and the filtrate was concentrated to give 3- (2 H - tetrazol-5-yl) -5- (trifluoromethyl) aniline (200mg, 0.781mmol, 92% yield): ¹ H NMR (400MHz, Methanol -d ₄ ) δ 7.96 (s, 1H), 7.71 (s, 1H), 7.32 (s, 1H). ES-LCMS (m/z) 230 (M+H).

Step 6: N- (3-(2H-tetrazol-5-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-) Oxybenzyloxy)pyridin-3-yl)-2-fluorophenyl)acetamide

In the presence of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (100 mg, 0.243 mmol) pyridine (10 mL) was added a mixture of 3- (2 H - tetrazol-5-yl) -5- (trifluoromethyl) aniline (55.7mg, 0.243mmol) and T ₃ P ^® (EA solvate) (220 mg of , 0.346 mmol). The mixture was stirred at 20 ° C for 1 h. LCMS showed the reaction was completed. Add ice - water to stop the reaction. The mixture is concentrated and the crude product is purified by TLC to yield N- (3-( 2H -tetrazol-5-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-B) Oxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (75 mg, 0.104 mmol, 42.9% yield): ¹ H NMR ( 400MHz, CD ₃ OD-d ₄ ) δ 8.62 (d, J = 4.4 Hz, 2H), 8.04 (d, J = 1.5 Hz, 1H), 7.94 (s, 1H), 7.61 (dd, J = 6.1, 7.8 Hz, 2H), 7.38 (d, J = 8.6 Hz, 3H), 6.92-6.85 (m, 3H), 5.35 (s, 2H), 4.15 (d, J = 6.8 Hz, 2H), 3.77 (s, 2H) ), 3.38-3.33 (m, 3H), 1.30-1.18 (m, 3H). ES-LCMS m/z 623 (M+H).

Step 7: N- (3-( 2H -tetrazol-5-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-yloxy)- 1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide

Containing N- (3-( 2H -tetrazol-5-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-) TFA (7.42 μL, 0.096 mmol) was added to a mixture of EtOAc (EtOAc). The mixture was stirred at 20 ° C for 1 h. LCMS showed the reaction was completed. The mixture was concentrated and the crude product was purified by preparative HPLC (column: ASB C18 150*25mm; mobile phase A: water + 0.1% HCl; mobile phase B: MeCN flow rate: 25 mL/min; gradient profile: 30- 66(B%)), yielding N- (3-( 2H -tetrazol-5-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6) -Phenoxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide (5.12 mg, 10.01 μmol, 20.8% yield): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.83 (br.s., 1H), 11.33 (s, 1H), 10.85 (s, 1H), 8.69-8.57 (m, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 7.47 (d, J =11.7 Hz, 1H), 7.42-7.27 (m, 3H), 7.12 (br.s., 1H), 4.03 (d, J = 6.8 Hz, 2H), 3.79 (s, 2H), 1.31 (t, J = 6.8 Hz, 3H). ES-LCMS m/z 503 (M+H).

Example 45: 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (1- methyl Base-1 H -pyrazol-4-yl)-5-(trifluoromethyl)phenyl)acetamide hydrochloride

Step 1:1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -pyrazole

Take 4-bromo-1-methyl-1 H -pyrazole (2g, 12.42mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2 '-(1,3,2-dioxaborolane) (3.47 g, 13.66 mmol), KOAc (2.438 g, 24.84 mmol), PdCl ₂ (dppf) (0.909 g, 1.242 mmol), 4-two The alkane (20 mL) suspension was heated to 100 ° C for 5 h under nitrogen. The mixture was concentrated and the residue was extracted using DCM (15 mL x 2). The organic extract was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated, and then the crude product was purified by silica gel column chromatography (10% EA: 90% petroleum ether, 4 g vermice column). All the fractions containing the product (EA: petroleum ether = 1:1, R _f = 0.3) were judged by TLC to be combined and concentrated to give 1-methyl-4-(4,4,5,5-four as a yellow solid. Methyl-1,3,2-dioxaborolan-2-yl)-1 H -pyrazole (700 mg, 3.36 mmol, 27.1% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77 (s, 1H), 7.66 (s, 1H), 3.92 (s, 3H), 1.32 (s, 12H). ES-LCMS m/z 209 (M+H).

Step 2: 1-Methyl-4-(3-nitro-5-(trifluoromethyl)phenyl)-1 H -pyrazole

Take 1-bromo-3-nitro-5-(trifluoromethyl)benzene (1 g, 3.70 mmol) of 1,4-two A suspension of alkane (12 mL) and water (4 mL) was added to 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- 1,2- H -pyrazole (0.771 g, 3.70 mmol) of 1,4-two A solution of alkane (12 mL) and water (4 mL). PdCl ₂ (dppf) (0.271 g, 0.370 mmol) and Cs ₂ CO ₃ (2.413 g, 7.41 mmol) were added and the mixture was heated at 100 ° C for 20 min. The cooled mixture was cooled to room temperature. The solution was then concentrated, and dissolved points between EA and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by column chromatography (PE/EA = 1:1). All the fractions containing the product (PE/EA = 5:1, R _f = 0.3) were judged by TLC to be combined and concentrated to give 1-methyl-4-(3-nitro-5-(3) Fluoromethyl)phenyl)-1 H -pyrazole (300 mg, 1.106 mmol, 29.9% yield): ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.47 (s, 1H), 8.31 (s, 1H), 7.99 (s, 1H), 7.89 (s, 1H), 7.81 (s, 1H), 4.01 (s, 3H). ES-LCMS m/z 272 (M+H).

Step 3: 3-(1-Methyl-1 H -pyrazol-4-yl)-5-(trifluoromethyl)aniline

Add Pd/C to a suspension of 1-methyl-4-(3-nitro-5-(trifluoromethyl)phenyl)-1 H -pyrazole (300 mg, 1.106 mmol) in MeOH (10 mL) (118 mg, 1.106 mmol). The mixture was hydrogenated at 40 psi and 28 ° C under H ₂ atmosphere for 12 h. The solution was then filtered and concentrated to give 3-(1-methyl- 1H -pyrazol-4-yl)-5-(trifluoromethyl)phenylamine (240 mg, 0.995 mmol, 90% yield). TLC (PE/EA = 1:1, _Rf = 0.3): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.98 (s, 1H), 7.81 (s, 1H), 7.16 (d, J = 7.3 Hz, 2H), 6.88 (s, 1H), 3.92 (s, 3H). ES-LCMS m/z 242 (M+H).

Step 4: 2- (4- (5-ethoxy-6 - ((4-methoxybenzyl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (3- ( 1-methyl-1 H -pyrazol-4-yl)-5-(trifluoromethyl)phenyl)acetamide

Containing 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl at 27 ° C under nitrogen atmosphere a solution of acetic acid (100 mg, 0.243 mmol) and 3-(1-methyl-1 H -pyrazol-4-yl)-5-(trifluoromethyl)aniline (58.6 mg, 0.243 mmol) in pyridine (2 mL) T ₃ P ^® (0.5 mL, 0.243 mmol) was added. The mixture was stirred at 27 ° C for 30 min. LCMS showed the reaction was completed. The mixture was then added to ice (5 g). The mixture was concentrated to give a residue. The residue was purified by preparative TLC (DCM / MeOH = 10:1, _Rf = 0.6) to yield 2-(4-(5-ethoxy-6-(4-methoxyphenyl) yl) oxy) pyridin-3-yl) -2-fluorophenyl) - N - (3- (1- methyl -1 H - pyrazol-4-yl) -5- (trifluoromethyl) phenyl Ethylamine (138 mg, 0.217 mmol, 89% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.09-7.93 (m, 2H), 7.87-7.76 (m, 2H), 7.69-7.52 (m) , 2H), 7.49-7.33 (m, 4H), 7.23 (dd, J = 7.8, 16.4 Hz, 2H), 6.91 (d, J = 7.9 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H) , 5.38-5.15 (m, 2H), 4.15 (d, J = 7.1 Hz, 2H), 3.94 - 3.60 (m, 8H), 1.42 (t, J = 6.8 Hz, 3H). ES-LCMS m/z 635 (M+H).

Step 5: (2-fluorophenyl 4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)) 2- - N - (3- (1- methyl -1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)acetamide hydrochloride

Add TFA solution (10% DCM solution, 10 mL) to 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2- Fluorophenyl) -N- (3-(1-methyl-1 H -pyrazol-4-yl)-5-(trifluoromethyl)phenyl)acetamide (138 mg, 0.217 mmol) in DCM ( 5 mL) in suspension. The mixture was stirred at 26 ° C for 3 h. The solution was then concentrated between 40 ° C and 45 ° C. The crude product was purified by preparative HPLC (instrument: DC/column: ASB C18 150*25mm / mobile phase A: water + 0.1% HCl / mobile phase B: MeCN / flow rate: 25 mL / min / gradient type Description: 18- 38(B%)), 2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl) -N as an off-white solid -(3-(1-Methyl-1 H -pyrazol-4-yl)-5-(trifluoromethyl)phenyl)acetamide hydrochloride (31.5 mg, 0.057 mmol, 26.3% yield) . TLC (DCM / MeOH = 10: 1, R f = 0.6): 1 H NMR (400MHz, CD 3 OD) δ 8.22 (s, 1H), 8.11-8.02 (m, 2H), 7.84 (s, 1H), 7.73 (d, J = 2.5 Hz, 2H), 7.60 (s, 1H), 7.55-7.43 (m, 3H), 4.30 (q, J = 6.7 Hz, 2H), 4.01 (s, 3H), 3.88 (s) , 2H), 1.51 (t, J = 7.0 Hz, 3H). ES-LCMS m/z 515 (M+H).

Example 46: N- (3-(2-(Dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6- side) Oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide

Step 1: N , N -Dimethyl-2-(3-nitro-5-(trifluoromethyl)phenoxy)ethylamine

A suspension of 2-(dimethylamino)ethanol (128 mg, 1.435 mmol) in DMF (5 mL) was added to 1-fluoro-3-nitro-5-(trifluoromethyl)benzene (200 mg, 0.956) Methyl) in DMF (5 mL) solution. K ₂ CO ₃ (264 mg, 1.913 mmol) was added, and the mixture was stirred at 80 ° C for 8 h. The mixture was cooled to room temperature. The solution was then concentrated, and dissolved in divided between ethyl acetate and saturated NaHCO ₃ solution. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (PE / EA = 5: 1, R f = 0.6) yielded the pale yellow solid of N, N - dimethyl-2- (3-nitro-5- (trifluoromethyl Phenoxy)ethylamine (75 mg, 0.270 mmol, 28.2% yield): ¹ H NMR (400 MHz, CD ₃ OD) δ 8.22-8.02 (m, 2H), 7.72 (s, 1H), 4.43 (t, J = 5.1 Hz, 2H), 3.26 (t, J = 4.9 Hz, 2H), 2.78-2.60 (m, 6H). ES-LCMS m/z 279 (M+H).

Step 2: 3-(2-(Dimethylamino)ethoxy)-5-(trifluoromethyl)aniline

Add a suspension of MeOH (5 mL) containing N , N -dimethyl-2-(3-nitro-5-(trifluoromethyl)phenoxy)ethylamine (75 mg, 0.270 mmol) to Pd/C (57.4 mg, 0.539 mmol) in MeOH (5 mL). The mixture was hydrogenated at 26 ° C for 3 h with H ₂ gas. The solution was then filtered and concentrated to give 3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenylamine (60.3 mg, 0.243 mmol, 90% yield). TLC (PE/EA = 1:1, _Rf = 0.5): ¹ H NMR (400 MHz, CD ₃ OD) δ 6.56 (s, 1H), 6.48 (s, 2H), 4.24 - 4.17 (m, 2H), 3.18 (t, J = 5.1 Hz, 2H), 2.67 (s, 6H). ES-LCMS m/z 249 (M+H).

Step 3: N- (3-(2-(Dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-() (4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide

Containing 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl at 27 ° C under nitrogen atmosphere Add acetic acid (100 mg, 0.243 mmol) to a solution of 3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenylamine (60.3 mg, 0.243 mmol) in pyridine (2 mL) T ₃ P ^® (0.5 mL, 0.243 mmol). The mixture was stirred at 27 ° C for 30 min. LCMS showed the reaction was completed. The mixture was then added to ice (10 mg). The precipitate was filtered and redissolved in DCM (5 mL). The solution was washed with water (5 mL x 2) and the combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was suspended in PE/EA (2:1, v/v, 8 mL) and stirred for 10 min. The solid was filtered and washed with EtOAc/EtOAc (2:1, v/v, 10mL) and dried in vacuo to give N- (3-(2-(dimethylamino)ethoxy)-5 -(Trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl Ethylamine (100 mg, 0.156 mmol, 64.1% yield). TLC (PE/EA = 1:1, R _f = 0.3): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.97-7.92 (m, 1H), 7.76 (br.s., 1H), 7.48-7.37 ( m, 7H), 7.04 (s, 1H), 6.91 (d, J = 8.6 Hz, 2H), 5.36 (s, 2H), 4.14 (q, J = 7.1 Hz, 4H), 3.86-3.78 (m, 5H) ), 2.97 (br.s., 8H), 1.42 (t, J = 6.9 Hz, 4H). ES-LCMS m/z 642 (M+H).

Step 4: N- (3-(2-(Dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-side) Oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide

In the presence of N- (3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-(( Add Pd/C (16.59 mg, 0.156) to a suspension of 4-methoxybenzyloxy)pyridin-3-yl)-2-fluorophenyl)acetamide (100 mg, 0.156 mmol) in MeOH (10 mL) Mm). The mixture was hydrogenated at 26 ° C for 3 h with H ₂ gas. The solution is then filtered and concentrated to yield a residue. The crude product was purified by preparative HPLC (instrument: Gilson GX281 / column: Gemini 150*25 mm*5 um / mobile phase A: water (0.05% ammonia solution) / mobile phase B: acetonitrile / gradient: 52-82 (B%) / flow rate: 25 mL / min / operating time: 10 min), yielding a white solid N- (3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2 -(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidine (41.16 mg, 0.079 mmol, 50.6% yield ). TLC (DCM / MeOH = 10:1, _Rf = 0.4): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.56-7.47 (m, 2H), 7.46-7.39 (m, 1H), 7.38-7.29 (m , 3H), 7.24 (d, J = 2.2 Hz, 1H), 6.96 (s, 1H), 4.19-4.09 (m, 4H), 3.80 (s, 2H), 2.81 (t, J = 5.3 Hz, 2H) , 2.36 (s, 6H), 1.47 (t, J = 6.9 Hz, 3H). ES-LCMS m/z 522 (M+H).

Bioanalytical method

The RET kinase inhibitory activity of the compounds of the invention was tested by RET kinase assay, cell-based transformation assay and cell-based proliferation assay.

RET kinase enzyme assay

The human RET kinase cytoplasmic domain (amino acid 658-1114, accession number NP_000314.1) was expressed as a N-terminal GST-fusion protein using a baculovirus expression system. GST-RET was purified by glutathione colloid chromatography. The RET Kinase Enzyme assay was performed in a 384-well format using a gradually increasing concentration of RET kinase inhibitor in a total volume of 10 μL in the following manner: When preparing a RET inhibitor compound assay plate, add 100 nL of different concentrations. RET inhibitors were plated into 384 well plates. Add 5 μL/well of 2X enzyme mixture (50 mM HEPES (4-(2-hydroxyethyl)-1-) Ethanesulfonic acid); 1 mM CHAPS (3-[(3-cholestyrylpropyl)dimethylammonio]-1-propane sulfonate); 0.1 mg/mL BSA (bovine serum albumin); 1 mM DTT (dithiothreitol); 0.2 nM RET kinase) into a 384-well plate, incubated at 23 ° C for 30 minutes, adding 5 μL / well of 2X substrate mixture (50 mM HEPES; 1 mM CHAPS; 0.1 mg / mL BSA; 20 μM adenosine triphosphate; 20 mM MgCl ₂ and 1 μM biotinylated peptide were incubated) and incubated at 23 ° C for 1 hour. Stop reaction/detection mixture with 10 μL/well 2X (50 mM HEPES; 0.1% BSA; 800 mM potassium fluoride; 50 mM EDTA (ethylenediaminetetraacetic acid); 200 抗 anti-phosphotyrosine antibody labeled with 铕 铕The dilution; 62.5 nM streptavidin-XL665) was incubated for 1 hour at 23 ° C and the data was read on a homogeneous time-difference fluorescence resolution reader. Using GraphPad Prism, the IC ₅₀ is substituted into an S- dose response curves.

RET kinase cell-based transformation analysis

The potency of the compounds of the invention in inhibiting the ability of constitutive RET kinase phosphorylation is determined in cell-based assays. TT cells (ATCC CRL-1803), a medullary medullary carcinoma cell line with constitutively activated RET kinase, were maintained in F12 Ganigh's medium at 150 ° C in a 150 cm ² dish at 37 ° C with 5% carbon dioxide. 10% fetal bovine serum, 1X Glutamax, 1X non-essential amino acid, 1X penicillin/streptomycin antibiotic). 1.0 E5 TT cells/well were plated in 96-well cell culture plates and allowed to attach overnight. TT cells were treated with different concentrations of RET inhibitor compounds, washed at 37 ° C with 5% carbon dioxide for 2 h, using ice-cold PBS (phosphate buffered saline), adding 200 μL of: 25 mM Tris HCl pH 7.5; 2 mM EDTA; 150 mM NaCl 1% sodium deoxycholate; 1% Triton X-100; 50 mM sodium beta glycerophosphate; 1 mM sodium orthovanadate; 1X phosphatase inhibitor cocktail #2 (Sigma #P5726); 1X phosphatase inhibitor cocktail #3(Sigma #P0044) Dissolve the cells with a 1X complete mini-type epase-free protease inhibitor (Roche #4693159001), incubate at -80 °C for 10 minutes, and thaw on ice. Add 100 μL of TT lysate to a 1:1,000 dilution of rabbit anti-RET antibody (Cell Signaling #7032) (blocked with 1X PBS); 0.05% Tween-20; 1% bovine blood Albumin overnight in a 96-well plate at 4 ° C overnight. The assay plate was washed 4 times with 200 μL of IX PBS; 0.05% Tween-20 and 100 μL of anti-phosphotyrosine detection antibody (Cell Signaling #7034) 1:1,000 dilution was added in sequence, and cultured at 37 ° C for 1 hour. . The assay plate was washed 4 times with 200 μL of IX PBS; 0.05% Tween-20 and 100 μL of anti-mouse immunoglobulin horseradish peroxidase conjugated antibody (Cell Signaling #7034) 1:1,000 dilution was added sequentially. Incubate at 37 ° C for 30 minutes. The assay plate was washed 4 times with 200 μL of IX PBS; 0.05% Tween-20, 100 μL of TMB (3,3',5,5"-tetramethylbenzidine) substrate (Cell Signaling #7004), at 37 ° C After incubation for 10 minutes, 100 μL of the stop reaction solution (Cell Signaling #7002) was added, and the absorbance at 450 nm was read on a luminometer. IC _{50 was} substituted into the S-type dose-effect curve using GraphPad Prism.

RET kinase cell-based proliferation assay

The efficacy of the compounds of the invention in inhibiting cell proliferation and cell viability is tested. TT cells (ATCC CRL-1803) (a medullary thyroid-like cancer cell line with constitutively activated RET kinase) were maintained in F12 Gann's medium maintained at 150 ° C in a 150 cm ² dish at 37 ° C and 5% carbon dioxide. (10% fetal bovine serum, 1X Glutamax, 1X non-essential amino acid, 1X penicillin/streptomycin antibiotic). 6.0E3 TT cells/well were added to 50 μL of medium in a 96-well cell culture plate and allowed to attach overnight. Serial dilutions of 50 μL of the RET inhibitor compound were added to 96-well plates containing cultured TT cells and cultured for 8 days at 37 ° C with 5% carbon dioxide. 50 μL of CellTiter-Glo (Promega #G-7573) was added, and the contents were mixed on a shaker for 1 minute, and then luminosity was read by EnVision (PerkinElmer) in the dark at 23 ° C for 10 minutes. Using GraphPad Prism, the IC ₅₀ is substituted into an S- dose response curves.

Biological data

Has one or more of the above compounds were tested RET assay embodiment of the invention, and the RET inhibitor is found that IC ₅₀ <10μM. The data for the determination of compounds in the human RET kinase assay are listed in Table 2 below: +=10 μM>IC ₅₀ >500 nM;++=500 nM IC ₅₀ >100nM; +++=IC ₅₀ 100nM. The data for the determination of compounds in the human RET kinase cell-based electroporation assay are listed in Table 3 below: +=10 μM>IC ₅₀ >500 nM;++=500 nM IC ₅₀ >100nM; +++=IC ₅₀ 100 nM; ND = not determined. The data for the determination of compounds in the human RET kinase cell-based proliferation assay are listed in Table 4 below: +=10 μM>IC ₅₀ >500 nM;++=500 nM IC ₅₀ >100nM; +++=IC ₅₀ 100 nM; ND = not determined.

In vivo colon hypersensitivity pattern

The potency of RET kinase inhibitor compounds can be in an in vivo mode of excessive colon sensitivity Determination (Hoffman, J. M. et al. Gastroenterology, 2012, 142: 844-854).

Claims (22)

A compound of formula (I): Wherein: R ¹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, hydroxy, (C ₁ -C ₆ ) Alkoxy, halo(C ₁ -C ₆ )alkoxy, (C ₃ -C ₆ )cycloalkoxy, amine, ((C ₁ -C ₆ )alkyl)amino-, or ((C ₁ -C ₆ )alkyl)((C ₁ -C ₆ )alkyl)amino-; each R ^{2 is} independently selected from the group consisting of halogen, (C ₁ -C ₆ )alkyl, Halogen (C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, cyano, hydroxy, (C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkoxy, (C ₃ -C ₆ )cycloalkoxy, amine, ((C ₁ -C ₆ )alkyl)amino-, and ((C ₁ -C ₆ )alkyl) ((C ₁ -C ₆ ) Alkyl)amino-; R ³ is phenyl or 5- or 6-membered heteroaryl, which may be optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halogen, (C ₁ -C ₆ An alkyl group, a halogen (C ₁ -C ₆ )alkyl group, a (C ₃ -C ₆ )cycloalkyl group, a cyano group, a 5- or 6-membered heteroaryl group, -OR ⁴ , and -CONR ⁵ R ⁶ ; Wherein the (C ₁ -C ₆ )alkyl group may be optionally substituted with a cyano group, a hydroxyl group, a (C ₁ -C ₄ ) alkoxy group, a halogen (C ₁ -C ₄ ) alkoxy group, or —NR ⁵ R ⁶ ; And wherein the 5- or 6-membered heteroaryl substituent is Need halogen, (C ₁ -C ₄₎ alkyl, or halo (C ₁ -C ₄₎ alkyl substituent; R ⁴ is hydrogen, (C ₁ -C ₆₎ alkyl, halo (C ₁ -C ₆₎ An alkyl group, a (C ₃ -C ₆ )cycloalkyl group, or a 4- to 6-membered heterocycloalkyl group; wherein the (C ₁ -C ₆ )alkyl group may optionally be via a cyano group, a hydroxy group, or a C ₁ -C ₄ ) alkoxy, halo(C ₁ -C ₄ )alkoxy, or -NR ⁵ R ⁶ substituted; and wherein the (C ₃ -C ₆ )cycloalkyl group may be independently selected from 1 or 2, respectively, as needed Substituted by the following substituents: (C ₁ -C ₄ )alkyl, halo(C ₁ -C ₄ )alkyl, hydroxy, hydroxy(C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkoxy And a halogen (C ₁ -C ₄ ) alkoxy group; and wherein the 4- to 6-membered heterocycloalkyl group may be optionally substituted with 1 or 2 substituents each independently selected from the group consisting of: (C ₁ -C ₄ And an alkyl group and a halogen (C ₁ -C ₄ ) alkyl group; the R ⁵ and R ⁶ groups are each independently selected from the group consisting of hydrogen, (C ₁ -C ₄ )alkyl, and halogen (C ₁ -C ₄ )alkyl; or R ⁵ and R ^{6 together} with the nitrogen to which they are attached represent a 5- or 6-membered saturated ring which may optionally comprise another hetero atom selected from the group consisting of oxygen, nitrogen and sulfur, wherein The ring may optionally be halogen, (C ₁ -C ₄ )alkyl, or halogen (C ₁ -C) ₄ ) an alkyl group; and n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof. A compound or a pharmaceutically acceptable salt according to claim 1 of the scope of the patent application, which is represented by the formula (II): Wherein: X is N or CR ¹⁰ ; R ¹ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, hydroxy, (C ₁ -C ₆ )alkoxy, halo(C ₁ -C ₆ )alkoxy, (C ₃ -C ₆ )cycloalkoxy, amine, ((C ₁ -C ₆ )alkyl)amine a base-, or ((C ₁ -C ₆ )alkyl)((C ₁ -C ₆ )alkyl)amino group; each R ^{2 is} independently selected from the group consisting of: halogen, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl, cyano, hydroxy, (C ₁ -C ₆ )alkoxy, halogen (C ₁ - C ₆ ) alkoxy, (C ₃ -C ₆ )cycloalkoxy, amine, ((C ₁ -C ₆ )alkyl)amino-, and ((C ₁ -C ₆ )alkyl) ( (C ₁ -C ₆ )alkyl)amino-; R ⁴ is hydrogen, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl Or a 4- to 6-membered heterocycloalkyl; wherein the (C ₁ -C ₆ )alkyl group may optionally be through a cyano group, a hydroxy group, a (C ₁ -C ₄ ) alkoxy group, a halogen (C ₁ -C ₄ Alkoxy, or -NR ⁵ R ⁶ substituted; and wherein the (C ₃ -C ₆ )cycloalkyl group may be substituted by 1 or 2 substituents each independently selected from: (C ₁ -C ₄ ) Alkyl, halo(C ₁ -C ₄ )alkyl, hydroxy, hydroxy (C ₁ -C ₄ An alkyl group, a (C ₁ -C ₄ ) alkoxy group, and a halogen (C ₁ -C ₄ ) alkoxy group; and wherein the 4- to 6-membered heterocycloalkyl group may be independently 1 or 2 independently Substituents selected from the group consisting of: (C ₁ -C ₄ )alkyl and halo(C ₁ -C ₄ )alkyl; R ⁵ and R ⁶ are each independently selected from the group consisting of: hydrogen, ( C ₁ -C ₄ )alkyl, and halo(C ₁ -C ₄ )alkyl; or R ⁵ and R ^{6 together} with the nitrogen to which they are attached represent a 5- or 6-membered saturated ring, which may optionally contain another a hetero atom selected from the group consisting of oxygen, nitrogen and sulfur, wherein the ring may be optionally substituted by halogen, (C ₁ -C ₄ )alkyl, or halo(C ₁ -C ₄ )alkyl; R ⁷ is hydrogen, halogen, Or (C ₁ -C ₄ )alkoxy; R ⁸ is hydrogen, halogen, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkyl, (C ₃ -C ₆ )cycloalkyl , cyano, 5- or 6-membered heteroaryl, -OR ⁴ , or -CONR ⁵ R ⁶ ; wherein the (C ₁ -C ₆ )alkyl group may optionally be cyano, hydroxy, (C ₁ -C ₄ Alkoxy, halo(C ₁ -C ₄ )alkoxy, or -NR ⁵ R ⁶ substituted; and wherein the 5- or 6-membered heteroaryl can be halogenated, (C ₁ -C ₄ ) alkane as desired a group or a halogen (C ₁ -C ₄ )alkyl group; R ⁹ is hydrogen, halogen, or halogen ( C ₁ -C ₄ )alkyl; R ¹⁰ is hydrogen, halogen, halo(C ₁ -C ₄ )alkyl, or 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is visible It is required to be substituted by halogen, (C ₁ -C ₄ )alkyl, or halo(C ₁ -C ₄ )alkyl; and n is 0, 1, or 2; however, the limitation is that when X is CR ¹⁰ , R ^7. At least one of R ⁸ , R ⁹ , and R ¹⁰ is hydrogen. A compound or a pharmaceutically acceptable salt according to claim 2, wherein R ⁷ is hydrogen or fluorine. A compound or a pharmaceutically acceptable salt according to claim 2 or 3, wherein R ⁸ is hydrogen, fluorine, chlorine, (C ₁ -C ₆ )alkyl, halo(C ₁ -C ₄ )alkyl, Cyano, (C ₁ -C ₄ )alkoxy, hydroxy(C ₂ -C ₄ )alkoxy-, (C ₁ -C ₄ )alkoxy(C ₂ -C ₄ )alkoxy-,amine (C ₂ -C ₄ )alkoxy-, ((C ₁ -C ₄ )alkyl)amino (C ₂ -C ₄ )alkoxy-, ((C ₁ -C ₄ )alkyl) ( (C ₁ -C ₄ )alkyl)amino (C ₂ -C ₄ )alkoxy-, or -CONH ₂ ; wherein the (C ₁ -C ₆ )alkyl group may optionally be cyano, hydroxy, (C ₁ -C ₄ ) alkoxy, amine, ((C ₁ -C ₄ )alkyl)amino-, or ((C ₁ -C ₄ )alkyl)((C ₁ -C ₄ )alkyl)amine Base-substituted. A compound or a pharmaceutically acceptable salt according to claim 4, wherein R ⁸ is hydrogen or (C ₁ -C ₆ )alkyl; wherein the (C ₁ -C ₆ )alkyl group may be cyano, Hydroxy, (C ₁ -C ₄ )alkoxy, amine, ((C ₁ -C ₄ )alkyl)amino-, or ((C ₁ -C ₄ )alkyl) ((C ₁ -C _{4 )} Alkyl)amino-substituted. A compound or a pharmaceutically acceptable salt according to claim 2 or 3, wherein R ⁹ is halo(C ₁ -C ₄ )alkyl. A compound according to claim 6 or a pharmaceutically acceptable salt, wherein R ⁹ is trifluoromethyl. A compound or a pharmaceutically acceptable salt according to claim 2 or 3, wherein X is CH. A compound or a pharmaceutically acceptable salt according to claim 2 or 3, wherein X is N. A compound or a pharmaceutically acceptable salt according to any one of claims 1 to 3 wherein R ¹ is (C ₁ -C ₄ )alkoxy. A compound or a pharmaceutically acceptable salt according to claim 10, wherein R ¹ is an ethoxy group. A compound or a pharmaceutically acceptable salt according to any one of claims 1 to 11, wherein n is 1 or 2, and each R ^{2 is} independently halogen. A compound according to claim 12 or a pharmaceutically acceptable salt, wherein each R ² is fluorine. A compound according to the first aspect of the patent application, which is: 2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl) - N- (6-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide; N- (6-ethoxy-5-(trifluoromethyl) Pyridin-3-yl)-2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide; 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (4- (3- hydroxy-2, 2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamidamine; 2-(4-(5-ethoxy-6-yloxy-1,6-dihydropyridine)- 2,3-difluorophenyl-3-yl)) - N - (4- ( 2- hydroxyethoxy) -3- (trifluoromethyl) phenyl) as acetamide; 2- (4- ( 5- ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (4- (3- hydroxy-2,2-dimethyl-propionic 3-(3-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-3 - fluorophenyl) - N - (4- (3- hydroxy-2,2-dimethylpropyl) -3- (trifluoromethyl) phenyl) as acetamide; N - (4- cyano - 3-(Trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-3-fluorophenyl) Guanamine; 2-(4-(5-B) 2,6-difluorophenyl-6-oxo-1,6-dihydropyridin-3-yl)) - N - (4- ( 2- hydroxyethoxy) -3- (trifluoromethyl Methyl)phenyl)acetamidamine; N- (4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-yloxy-1, 6-Dihydropyridin-3-yl)-2-fluorophenyl)acetamide; N- (6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridine 3-yl)-2-(4-(4-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidamine; 2-( 4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (4- methyl -1 H - imidazole -1-yl)-5-(trifluoromethyl)phenyl)acetamide; N- (6-(2-cyanopropan-2-yl)-5-(trifluoromethyl)pyridine-3- 2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidamine; 2-(4-( 5- ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (4- (2- hydroxyethoxy) 3- (tri Fluoromethyl)phenyl)acetamide; N- (6-(cyanomethyl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy)- 6-Sideoxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide; N- (6-(1-cyanoethyl)-5-(trifluoromethyl) Pyridin-3-yl)-2-(4-(5-ethoxy-6-side oxygen) 1,6-dihydro-pyridin-3-yl) -2-fluorophenyl) as acetamide; N - (4- chloro-3- (trifluoromethyl) phenyl) -2- (4- (5 -ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide; N- (4-((dimethylamino)methyl) -3-(Trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl) Acetamine; N- (3,4-dichlorophenyl)-2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2- fluorophenyl) as acetamide; 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (5 -(1,1,1-trifluoro-2-methylpropan-2-yl) Oxadiazol-3-yl) acetyl amine; 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamidamine; 2-(4-(5-ethoxy-6-yloxy-1,6-di) hydrogen pyridin-3-yl) -2-fluorophenyl) - N - (4 - ( (4- ethylpiperazin -1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide; N- (2,5-difluorophenyl)-2-(4-(5-ethoxy-6) -Sideoxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidamine; 4-(2-(4-(5-ethoxy-6-yloxy-1) ,6-dihydropyridin-3-yl)-2-fluorophenyl)ethylamino)-2-(trifluoromethyl)benzamide; N- (2,4-difluoro-5-( Trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide; N- (3,5-bis(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2 - fluorophenyl) as acetamide; or 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (2-Fluoro-5-(trifluoromethyl)phenyl)acetamide; or a pharmaceutically acceptable salt thereof. A compound according to the first aspect of the patent application, which is a 2-(4-(4-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl) - N -(3-(1,1,1-trifluoro-2-methylpropan-2-yl)iso Oxadiazol-5-yl) acetyl amine; 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3-(1,1,1-trifluoro-2-methylpropan-2-yl)iso Oxadiazol-5-yl) acetyl amine; 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3-(5-methyl-1,3,4- Diazol-2-yl)-5-(trifluoromethyl)phenyl)acetamidamine; 2-(4-(4-ethoxy-6-o-oxy-1,6-dihydropyridine-3 - yl) -2-fluorophenyl) - N - (5- (1,1,1- trifluoro-2-methylpropan-2-yl) iso Oxadiazol-3-yl) acetyl amine; 2- (4- (4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (6-(1-hydroxy-2-methylpropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamidamine; 2-(4-(4-ethoxy-6) --oxo-1,6-dihydropyridin-3-yl) -3-fluorophenyl) - N - (4- (3- hydroxy-2,2-dimethylpropyl) -3- (C Fluoromethyl)phenyl)acetamidamine; or 2-(4-(4-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)- N- (3-(trifluoromethyl)phenyl)acetamide; or a pharmaceutically acceptable salt thereof. A compound according to the first aspect of the patent application, which is: 2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl) - N- (3-(4-Methyl-1 H -pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamidamine; 2-(4-(5-ethoxy)- 6--oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (3- methyl -1 H - pyrazol-1-yl) -5- (trifluoromethyl)phenyl)acetamide; N- (3-(1 H -pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5- Ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamidamine; 2-(4-(4-ethoxy-6-sideoxy) 1,6-dihydro-pyridin-3-yl) -2-fluorophenyl) - N - (6- (1,1,1- trifluoro-2-methylpropan-2-yl) pyridine-3 Acetylamine; N- (4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-o-oxy-1,6-dihydrol) Pyridin-3-yl)-2-fluorophenyl)acetamidamine; 2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2- fluorophenyl) - N - (3- (2- morpholino-ethoxy) -5- (trifluoromethyl) phenyl) as acetamide; 2- (4- (4-ethoxy-6- -oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (1,1,1- trifluoro-2-methylpropan-2-yl) iso Oxadiazol-5-yl) acetyl amine; 2- (4- (5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (1-methyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1 H -pyrazol-5-yl)acetamidamine; 2-(4-(5 - ethoxy-6-oxo-1,6-dihydropyridin-3-yl) -2-fluorophenyl) - N - (3- (1,1,1- trifluoro-2-methyl Propane-2-yl)-1 H -pyrazol-5-yl)acetamide; N- (4-(2,2-difluoro-3-hydroxypropyl)-3-(trifluoromethyl)benzene 2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide; N- (3-( 2 H -tetrazol-5-yl)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridine-3 -yl)-2-fluorophenyl)acetamidamine; 2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridin-3-yl)-2-fluorophenyl ) - N - (3- (1- methyl -1 H - pyrazol-4-yl) -5- (trifluoromethyl) phenyl) acetyl amine; or N - (3- (2- (two Methylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-o-oxy-1,6-dihydropyridine-3- (2-fluorophenyl)acetamidamine; or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient. The pharmaceutical composition according to claim 17 of the patent application is for the treatment of intestinal irritation. The pharmaceutical composition according to claim 17 of the patent application is for the treatment of cancer. A compound or a pharmaceutically acceptable salt according to any one of claims 1 to 16 which is for medical use. A use of a compound or a pharmaceutically acceptable salt according to any one of claims 1 to 16 for the manufacture of a medicament for the treatment of intestinal irritation. A use of a compound or a pharmaceutically acceptable salt according to any one of claims 1 to 16 for the manufacture of a medicament for the treatment of cancer.